Aspek Psikiatrik Pada Penderita SLE

Aspek psikiatrik pada penderita SLE
Jurnal 1
Clin Dev Immunol. 2013; 2013: 270878.
Published online 2013 June 20. doi: 10.1155/2013/270878
PMCID: PMC3705842
The Correlations of Disease Activity,

Socioeconomic Status, Quality of Life,
and Depression/Anxiety in Chinese
Patients with Systemic Lupus
Erythematosus
Biyu Shen, 1 , 2 Wei Tan, 3 Guijuan Feng, 3 Yan He, 1 Jinwei Liu, 1 Weijun Chen, 1 Xiaoqin
Huang, 1 Zhanyun Da, 3 Xujuan Xu, 2 Hong Liu, 3 and Zhifeng Gu 3 ,*
Author information Article notes Copyright and License information
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Abstract
The prevalence of psychological problems is frequent in systemic lupus erythematosus
(SLE) patients and appears to be increasing. The current study investigated the
relationship among disease parameters, quality of life, and the psychological status in
Chinese patients with SLE. A self-report survey design was administered to 170 SLE
patients and 210 healthy individuals using the Self-Rating Anxiety Scale, the Self-Rating
Depression Scale, and the Short Form 36 health survey (SF-36). Our results showed that
20.3% SLE patients had anxiety, and 32.9% had depression, which were significantly
higher than the control group (7.1%, 14.3%, resp.). And there were significant
correlations among socioeconomic status (SES), disease activity, and anxiety/depression
in SLE patients. Meanwhile, SF-36 analysis results revealed that VT, PF, and RP scales
were the most powerful predictors of anxiety of SLE patients, and SLEDAI, VT, PF, SF,
and RE domains were significantly accounted for anxiety. In summary, there were
significant relationships among disease parameters, quality of life, and anxiety/depression
in Chinese SLE patients. Therefore, it is necessary to have psychiatric and psychological
evaluations and formulate an integrated approach for managing mental health in Chinese
lupus patients, especially those who have high disease activity, low SES, and poor quality
of life.
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1. Introduction
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that

may affect multiple organ systems, including the central nervous system (CNS) [1].
Psychiatric symptoms are present in the majority of patients with SLE, among which
major depression is the most common psychiatric manifestations [2]. Depression
presented in 11%39% of patients may be the initial symptom before the diagnosis of
SLE [3]. It was reported that there were 4 times higher prevalence of depression in SLE
compared to a matched, non-SLE population. In addition, anxiety is quite common in
SLE patients, often as a reaction to the illness. Ainiala and colleagues have reported that
the anxiety disorders were twice as prevalent among SLE patients as compared to the
controls [4].
Even though SLE presents accompany with a wide variety of treatable psychiatric
symptoms, such as depression and anxiety, they rarely seek and receive adequate
treatment [5]. Overlooking anxiety and depression may have severe consequences for the
patients, such as increased incidence of cardiovascular disease [6], myocardial infarction
[7], suicidal ideation [8, 9] and death [10], decreased quality of life [11, 12], disability,
and the loss of employment. Anyone, in turn, can worsen anxiety and depression
symptoms [5].
The pathogenesis of psychiatric symptoms in lupus is still not well understood, but in
which genetic and environmental factors may play a pivotal role. Depression and anxiety
may also be present as a reaction to a serious recurring, painful illness, which is
associated with visible symptoms such as insomnia, fatigue, and limited functioning [13,
14]. Socioeconomic status (SES) is broadly employed in health research, signaling the
importance of socioeconomic factors for health outcomes. Low SES is generally
associated with high psychiatric morbidity, depression [15], and mortality [16]. Whether
depression and anxiety are associated with lupus activity remains debatable.
There are several studies focus on psychological problems in China lupus patients. A
study from Hong Kong has found that anxiety disorder was present in 22% SLE patients,
and 18.2% had depression [17]. A study from Anhui medical university has reported that
the prevalence of depression was 59.3% and correlated with suicidal ideation in SLE
patients [8]. But there are few studies that focus on disease parameters, quality of life,
and depression/anxiety in SLE patients from China mainland.
Thus, the aim of this study was to examine the relationship among disease parameters,
quality of life, and the psychological status in Chinese patients with SLE. Moreover, we
wished to ascertain the possible risks of anxiety and depression.
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2. Patients and Methods

2.1. Participants
SLE patients were recruited from Affiliated Hospital of Nantong University between
January 2010 and July 2011. A total of 170 SLE patients and 210 healthy individuals
were consecutively invited to participate in a single-center cross-sectional study. Healthy
individuals were used as the control group. All patients fulfilled the 1997 American
College of Rheumatology (ACR) revised criteria for the classification of SLE. Patients
were excluded based on the following: (1) they did not complete questionnaire; (2) they
had comorbidities (e.g., serious infections or cardiac, respiratory, gastrointestinal,
neurological, or endocrine diseases) that could influence SLE activity. Control subjects
were excluded if they exhibited current or history of other systemic diseases or
psychiatric disorders. This study was approved by the Ethics Committee of Affiliated
Hospital of Nantong University, and written informed consent was obtained from all
participants.
2.2. Measures of Clinical Variables

The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was used to
measure disease activity [18].
2.3. The Revised Self-Rating Anxiety Scale (SAS) [19]

SAS was used to evaluate the level of anxiety-related symptoms during the week prior to
the survey. This self-administered test has 20 questions, with 15 items reflecting
increasing anxiety levels and 5 questions reflecting decreasing anxiety levels. Each
question was scored on a scale from 1 to 4 (rarely, sometimes, frequently, and always).
The scores ranged between 20 and 80: scores greater than 70 suggest severe anxious
symptoms, scores between 60 and 69 indicate moderate to marked anxiety, scores
between 50 and 59 suggest minimal to mild anxiety, and scores less than 50 indicate no
anxious symptoms.
2.4. The Revised Self-Rating Depression Scale (SDS) [20]

SDS is a 20-item questionnaire designed to assess mood symptoms over the past week
(e.g., I feel downhearted, blue and sad). Each item is scored on a Likert scale ranging
from 1 to 4; scores greater than 70 suggest severe depressive symptoms, scores between
60 and 69 indicate moderate to marked depression, scores between 50 and 59 suggest
minimal to mild depression, and scores less than 50 indicate no depressive symptoms.
2.5. Measure of the Quality of Life [21]

The patient's general health status was measured using the Short Form- (SF-) 36
questionnaire, which measured eight multi-item dimensions: physical functioning (PF, 10
items); role limitations due to physical problems (RP, four items); role limitations due to
emotional problems (RE, three items); social functioning (SF, two items); mental health
(MH, five items); energy/vitality (VT, four items); body pain (BP, two items); and general
health perception (GH, five items). For each dimension, item scores were coded,
summed, and transformed on a scale from 0 (worst possible health state measured by the
questionnaire) to 100 (best possible health state).
2.6. Statistical Analysis

The data were expressed as means SDs for continuous variables and as frequencies (%)
for categorical variables. The Statistical Package for SPSS 18.0 was used for all data
management and analyses. Descriptive analyses were performed to investigate the
participants' characteristics. Student's t-test was used in independent groups for
parametric variables, and the Spearman's correlation analysis was used to assess the
correlation between parametric variables. Stepwise regression analyses were conducted
for SAS and SDS scores separately to explore the significant predictors of dimorphic
concerns. We considered P < 0.01 and P < 0.001 to be highly statistically significant and
P < 0.05 to be statistically significant.
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3. Results
3.1. Sample Characteristics
12 SLE patients and 14 healthy individuals did not complete the questionnaire, resulting
in the enrollment of 158 SLE patients (14 males and 144 females) and 196 healthy
individuals (20 males and 176 females) in the current study. Table 1 showed their
demographic data, medical and psychological variables. There was no significant
difference in the ages, genders, marital status, education, work status, income/person, and
menstrual history between the SLE patients and the controls. The SAS and SDS scores
were significantly higher in the SLE group compared to the control group. According to
the cut-off scores, anxiety disorder was present in 32/158 (20.3%), and 52/158 (32.9%)
had depression, which were significantly higher than the healthy group ((14/196, 7.1%)
and (28/196, 14.3%), resp.) (P < 0.01). As shown in Table 2, the scores of all the 8 scales
were lower in SLE patients compared with healthy individuals. There was significant
difference between physical functioning (PF), role limitations due to physical problems
(RP), role limitations due to emotional problems (RE), mental health (MH), and
energy/vitality (VT) in SLE and control group (P < 0.05).
Table 1
Demographic, psychological, and disease characteristics in SLE patients and controls.
Table 2
Correlations between psychological scores, disease parameters, and quality of life in SLE
patients.
3.2. Correlations between Psychological Scores, Disease Parameters, and

Quality of Life in SLE Patients
Previous studies have shown that low socioeconomic factors (SES) were generally
associated with high psychiatric morbidity, depression, and anxiety [22]. As show in
Table 3, we have found that there were significant correlations between SES (low
education, work status, and income) and anxiety/depression in SLE patients. In addition,
gender and menstrual history were some examples of depression risk factors. There was a
significant positive correlation between anxiety/depression severity (assessed using
SAS/SDS score) and disease activity (SLEDAI score). Previous studies have found that
impaired quality of life and functional disability were independent risk factors of
psychological disorders [12]. In the present study, we found that all the 8 scales of SF-36
domains and PCS/MCS were significantly correlated with SAS and SDS scores except
body pain (BP) scale (P < 0.05).
Table 3
Disease status and quality of life in the anxious and depressed subgroups.
3.3. Stepwise Regression Analysis for Anxiety and Depression

Multiple stepwise regression analysis revealed that VT, PF, and RP scales of SF-36 were
the most powerful predictors of anxiety of SLE patients (Table 4). Meanwhile, SLEDAI,
VT, PF, SF, and RE domains of SF-36 were significantly accounted for anxiety (Table 5).
Table 4
Stepwise regression analyses of medical and psychological variables and their
relationship to SAS in SLE patients.
Table 5
Stepwise regression analyses of medical and psychological variables and their
relationship to SDS in SLE patients.
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4. Discussion
The present study confirmed that Chinese SLE patients were more likely to suffer from
anxiety and depression than healthy individuals. Psychological problems significantly
correlated with SES, disease status, and quality of life. SLE patients with anxiety and
depression were in low SES and had worse disease status, lower quality of life. Among
the assessed parameters, VT, PF, and RP scales of SF-36 were major contributors to
anxiety in SLE patients, while disease activity and VT, PF, SF, and RE domains of SF-36
contributed to depression.
SES is broadly employed in health research, signaling the importance of socioeconomic
factors for health outcomes. Previous study has found that poorer coping styles, ongoing
life events, stress exposure, and weaker social support were some examples of depression
risk factors that were more prevalent in lower SES groups [23]. Regarding the direction
of the association for SES and depression, results more consistently supported the idea
that causation (low SES increases risk of depression) outweighed selection (depression
hinders social mobility), although both directions may operate simultaneously [17]. It is
well known that SES is multifactor. Occupation [5, 24, 25], education, and income [26]
were frequently used as measures of SES. With notable exceptions, there were significant
relationships between anxiety/depression and SES [5]. There was a substantial body of
research linking SES, anxiety/depression, and SLE. Waheed et al. found that educational
qualification had significant association with anxiety and depression. Marital status,
gender, economic activity, and monthly family income had no effect on the frequency of
anxiety and depression [27]. In the present study, we have found that SLE patients who
had low education, unemployed, and low income were prone to anxiety/depression.
Female gender and younger age have well-known associations with depression and
confound the SES anxiety/depression relationship in SLE [28]. In the present study,
gender was independently associated with depression in SLE. Interestingly, we have
found that there were significant correlation between abnormal menstrual history and
depression. Whether anxiety/depression is associated with lupus activity remains
debatable. Walker SE and colleagues reported that the anxiety severity did correlate
positively with SLE activity [29]. Nery et al. reported a significant positive correlation
between depression and disease activity [30]. In contrast, other studies reported that there
was not relationship between lupus activity and presence of a major depressive episode
[31]. In the present study, our group found significant positive correlation between
anxiety/depression and disease activity. Health-related quality of life in lupus was found
to be significantly worse in comparison with control group. Recent study reported that
SLE patients who had significantly poorer health-related quality of life were significantly
more depressed and anxious than their healthy counterparts [11]. We have also found the
PCS and MCS and all 8 domains of SF-36 except BP were significantly worse than
control subjects. The results were similar with the study from Hong Kong. We have also
found that the SLEDAI scores were a strong predictor of depression in patients with SLE.
Notably, the results of the present study demonstrated that anxiety in Chinese SLE
patients differs from SLE patients in other countries. This could be explained by some
cultural features which may influence mental disease diagnosis and management in
China. We have found that the prevalence of depression was higher than Hong Kong, and
it might be due to cultural differences and SES such as income and medical insurances
policy.
In order to identify which variables were most significantly correlated with anxiety and
depression, stepwise regression analysis was used. We have found that VT, PF, and RP
scales of SF-36 were the most powerful predictors of anxiety of SLE patients.
Meanwhile, SLEDAI, VT, PF, SF, and RE domains of SF-36 were significantly accounted
for anxiety. It could be explained that impaired quality of life and functional disability
were independent risk factors for psychological disorders.
A possible limitation of the present study was that all patients involved in the survey were
from only one center and its failure to differentiate between men and women; the gender
differences in SLE patients require further analysis in a future study. Another limitation
of the study was that we did not detect the impact of proinflammatory cytokines on
depression. Recent study reported that higher serum TNF- level was independently
associated with poorer health-related quality of life and more severe depressive
symptoms in SLE patients in Singapore [11].
In summary, our study indicated that psychological problems were frequent in Chinese
SLE patients. Severe disease status and reduced quality of life significantly correlated
with anxiety and depression. Disease activity was higher in anxious and depressed
subgroups. Quality of life was decreased in depressed subgroups. Impaired mental health
and pain were the most powerful predictors of anxiety and depression. Low SES was
independently associated with poor mental health. These findings confirmed the
importance of psychosocial interventions in combination with medical therapy for SLE

patients.
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Authors' Contribution
Biyu Shen and Wei Tan contribute equally to this work.
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Acknowledgments
The authors want to thank Liren Li, Xinghang Zhu, Genkai Guo, Jie Qian, Haixia Cao,
and Yunfei Xia for their assistance with this paper. This work was supported by the
National Natural Science Foundation of China (Grant no. 81172841), the Natural Science
Foundation of Jiangsu Colleges and Universities Grant no. 09KJB320010, Top Six
Types of Talents Financial Assistance of Jiangsu Province Grant no. 6, and Jiangsu
province's Outstanding Medical Academic Leader Program (LJ201136). This work was
also supported by the Science Foundation of Nantong City Grant no. HS2011054, the
Beijing Medical Award foundation (FSMYYSNT-001), a project of College graduate
research and innovation of Jiangsu Province (CXLX12-0891), the Nantong University
Graduate Innovation Program (YKC12037), the Nantong Science and Technology Board
(HS12966), and the Bureau of Jiangsu Province (Z2010005), Preventive Medicine
Research of Jiangsu province (Y2012083).
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Jurnal 2
Neuropsychiatr Dis Treat. 2013; 9: 799804.
Published online 2013 June 5. doi: 10.2147/NDT.S44248
PMCID: PMC3678948
Prevalence and predictors of depression

in patients with systemic lupus
erythematosus: a cross-sectional study
Benchalak Maneeton,1 Narong Maneeton,1 and Worawit Louthrenoo2
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Abstract
Objective
The purpose of this study was to estimate the prevalence and examine the predictors of
depression in patients with systemic lupus erythematosus (SLE).
Methods
This cross-sectional study was conducted in the rheumatology clinic of a university
hospital. All SLE patients that met the revised American College of Rheumatology
(ACR) classification were included in the study. Sociodemographic data and medications
were recorded. Disease activity for SLE was assessed with the Mexican-SLE Disease
Activity Index (Mex-SLEDAI). All subjects were screened for anxiety and depression by
using the Hamilton Anxiety Rating Scale (HAM-A) and the 17-item version of the
Hamilton Depression Rating Scale (HAM-D17). Multiple linear regression analyses were
used to determine predictors of depressive disorder.
Results
A total of 62 SLE (61 females and 1 male) patients participated in the study. Based on
HAM-D17 and HAM-A, rates of depression and anxiety in SLE patients were 45.2% and
37.1%, respectively. The multiple linear regression analysis revealed that HAM-A score
and younger age were significant predictors of depression in SLE patients.
Conclusion
The findings suggest that depression and anxiety are common in SLE patients. In
addition, higher levels of anxiety and a younger age may increase the risk of depression.
Because of the small sample size, further studies should be conducted to confirm these
results.
Keywords: systemic lupus erythematosus, depression, anxiety disorder
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Introduction
Depression is common in the general population. A meta-analysis of data obtained from
several countries showed that 1-year and lifetime prevalence rates of major depressive
disorder (MDD) were 4% and 7% respectively.1 A higher prevalence rate of depression is
found in patients with a chronic medical illness. Recently, a study of patients with
systemic sclerosis showed that 1-year and lifetime prevalence rates of MDD were 11%
and 23% respectively.2 Those rates are approximately twice that of the general
population.2 Similarly, recent evidence suggests that the prevalence of depression in
cancer patients is as high as 30% and depressive severity is associated with severity of
physical pain.3
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which usually

affects multiple organ systems including the central nervous system.4,5 Therefore, it can
cause several neuropsychiatric syndromes, including depression.6,7 Recent evidence
suggests that the prevalence of depression in SLE patients is between 11.5% and 47%.8
13 In addition, a recent study suggests that severity of depression increases with more
severe disease activity of SLE.14 The extended life span of SLE patients from current
advances in medicine leads these patients to encounter a relapsing and remitting course of
the disease and adverse events from several treatments that may deteriorate their quality
of life and intimate relationships, and may precipitate depression.15,16 In addition, the
burden of SLE comorbid with depression may increase the risk of suicide.17
Although awareness of psychiatric complications has increased among physicians and
other health professionals, little research focuses on depressive aspects of SLE.
Therefore, the aim of the current study was to determine the prevalence of depressive
disorders in SLE patients and to identify risk factors.
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Material and methods

Patients
The study used the clinical data from the cross-sectional SLE study. Patients were
recruited from the Rheumatology Clinic of University Hospital, Chiang Mai University,
Thailand.18 All SLE patients, aged 1860 years, fulfilling the inclusion criteria for their
diagnosis based on the revised American College of Rheumatology (ACR)
classification19 were included in this study. Exclusion criteria included unstable medical
conditions, impaired consciousness, a significant hearing impairment, any degree of
visual impairment, or lack of the necessary communication skills to ensure the reliability
of test scores. The study was approved by the Medical Ethical Committee of Chiang Mai
University, and all subjects gave an informed consent.
Evaluation
Clinical characteristics
The rheumatologist (WL) reviewed a series of interviews, demographic data, and all
medical records; did physical examinations and monitored laboratory tests (complete
blood count, erythrocyte sedimentation rate, urinalysis, liver function tests, and serum
creatinine). The history of central nervous system (CNS) involvement such as a history of
seizures and any episode of delirium was also noted. The Mexican-SLE Disease Activity
Index (Mex-SLEDAI), a standardized index derived from clinical and serological
variables,20 was used to assess disease activity twice (firstly at the time of SLE diagnosis
and later on screening for study inclusion).
Assessment of depressive and anxiety disorders The psychiatrists evaluated for levels of
anxiety and depression in all patients using the 17-item version of the Hamilton
Depression Rating Scale (HAM-D17)21 and the Hamilton Anxiety Rating Scale (HAMA).22 Based on the HAM-D17, depression is defined as scores equal to 11 or more.21,23
Cut-off scores for anxiety, as measured by the HAM-A, are as follows: 013 no anxiety,
1417 mild anxiety, 1824 moderate anxiety, and 2530 severe anxiety.22
Statistical analysis
Descriptive analysis of sociodemographic data and clinical variables were undertaken.
The dependent variable in the present study was depression. The Students t-test and
Mann Whitney U-test (for continuous variables), and the Fishers exact test and a Chisquared test (for categorical variables) were used to examine the significant association
(contingency) of independent variables between the depressive and nondepressive
groups. Multivariate analysis was performed by using the linear regression model. Each
independent factor which was statistically significant at the bivariate level (P < 0.1) was
included in the analysis. We then developed a final model that combined patient
characteristics, considering inclusion variables independently associated with depressive
disorder in the SLE patients. All data were analyzed by using the SPSS (version 17; SPSS
Inc, Chicago, IL, USA).
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Results
The 62 SLE patients (female vs male, 61:1) were included in this analysis. Mean age
standard deviation (SD) of those patients was 31.8 9.0 years. Of those, 33.9% of them
had completed 13 years of education, while the rate of unemployment was 40.3%. Mean
SD disease duration of total patients was 73.7 57.8 months. Mean SD of the HAMA and HAM-D17 scores of those patients were 12.4 9.4 and 10.6 8.8 respectively.
Based on HAM-A score, 37.1% of the patients had an anxiety disorder. Of all anxious
patients, 30.4%, 34.8%, and 34.8% of them had severe, moderate, and mild anxiety,
respectively. Disease activity indices at the first time of SLE diagnosis and at the time of
interview were 13.1 5.2 and 3.5 3.7, respectively. Forty-five percent of total patients
experienced CNS involvement, frequently receiving various medications to treat SLE at
any potential time point in the course of their illness, including prednisolone,
methotrexate, chloroquine, or cyclophosphamide.
Based on the HAM-D17 score, 45.2% of the patients were defined in the depressive
group. Table 1 compares the clinical characteristics between depressive and nondepressive groups of the SLE patients. Comparison of the two groups, by sex, education
duration, disease duration, disease activity and current medications showed no significant
differences. In addition, several medications, administered for SLE treatment, were not
significantly different in the two groups in terms of number, type, duration and dose (see
Table 2). Significant differences (P < 0.05) were found among the two groups in the
HAM-A score (P < 0.001) and unemployment (P = 0.003). As a result, these factors were
included in multiple linear regression analysis as independent variables. Moreover, other

factors which had significant differences (P < 0.1) were also included in the analyses
(age, history of CNS involvement and a number of lifetime medications). The findings
suggest that depression severity are significantly associated with the HAM-A and age
(adjusted R square = 0.799, Durbin-Watson = 1.796) (see Table 3).
Table 1
Characteristics of SLE patients
Table 2
Mean doses of each drug treatment for SLE patients with/without depression
Table 3
Multiple linear regression analysis of predictors for depressive disorder in SLE
patients
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Discussion
This study suggests that the prevalence of depression and anxiety in SLE patients is high.
The point prevalence of depressive and anxiety disorders in SLE patients are 45.2% and
37.1%, respectively. Depression severity is associated with higher anxiety and younger
age.
In general, prevalence of psychiatric manifestations is high in the SLE patients.6,24,25
Of those, depression is one of the most common mental illnesses.26 Similar to present
findings, the recent studies suggest that the point prevalence of depressive disorder in
SLE is up to 39%,27 while the lifetime prevalence is up to 69%,28,29 which is far more
prevalent than that of the general population in which the point and lifetime prevalence is
6.1% and 10.3%, respectively.1 The high morbidity of depression in SLE warrants
continuing research and expansion of efforts in the clinical setting to optimize treatments.
Compared with the general population, anxiety is another common psychiatric
manifestation in SLE populations. A recent study found that the 30 day and lifetime
prevalence for anxiety in SLE patients, including agoraphobia without panic disorder,
generalized anxiety disorder and other anxiety disorder, were 46.5% and 52.1%,
respectively.28 Similarly, another group found that the prevalence of anxiety, as
measured by the HAM-A, was as high as 65.7%.30 Because of the high prevalence of
anxiety, individual SLE patients should undergo psychiatric assessment for anxiety.
In general, the relationship between depression and anxiety in patients across different
ages with chronic somatic disease has been reported. Recently, the evidence suggests that
the anxiety trait is a significant determinant of depressive symptoms in patients with
breast cancer.31 The recent study of patients with pain symptoms also suggests that
anxiety and depression may correlate positively.32 In addition, the significant
relationship between them has been reported in the advanced cancer patients with median
age of 59 years (range 2091 years).33 Like the present findings, the relationship
between both anxiety and depression in SLE patients was also noted in the previous
study.34 Thus, all patients with chronic medical illness, including SLE patients, should be
also evaluated for depression and anxiety.
Based on these findings, a younger age of patients with SLE is also associated with
depression. Similarly, it was previously found that in pediatric inpatients with SLE there
was a higher prevalence of major depressive disorder.35 Those with early onset SLE may
also have difficulties in living with SLE-related disability. Long-term distress in adjusting
to their lives with disability may play a role in causing depression. For anxiety, it is a
symptom commonly found in depressed patients. In any event, depressive and anxious
functional brain pathology has substantial overlap in their functional correlates and might
be part of the same process. Therefore, screening for anxiety in SLE younger patients
may be beneficial in term of evaluation and management.
Disease activity indicating severity of SLE relates to depression. A study of 71 female
patients with SLE found that disease activity was associated with depression severity
measured by the Montgomery-Asberg Depression Rating Scale (MADRS).36
Unfortunately, the findings from our study did not show this association between them.
Reasons for these differing results are unclear. However, one possible explanation for the
different findings is the potentially confounding influence of prednisolone, a medication
which can induce depression.37 Mean doses of prednisolone in a previous study were
18.28 mg/day for the major depressive disorder (MDD) group and 15.0 mg/day for the
non-MDD group,36 while mean doses of this medication in our study were less than that
of a previous study.36 Further research with a larger sample size and well-controlled
study methodology may clarify these phenomena.
CNS involvements in SLE may be one of the major causes of morbidity and mortality. It
is also associated with psychiatric manifestations, particularly in psychosis (23%).38 A
previous study in childhood SLE suggests that mood disorder is not a common
neuropsychiatric manifestation in SLE patients with CNS involvement,39 which is
similar to present findings. So far, the explanation has been unclear, however, mood
disorder in those patients, especially in depression, may come from several causes,
including pathology in CNS or psychological reaction of the disease.
There are some limitations in this study. Firstly, the findings resulted from a small sample
size, and therefore, it should be interpreted with caution. To confirm these analyses, a
large sample size study should be conducted. Secondly, since there is high prevalence of
SLE in women, nearly all participants in this study were female. Generalization from this
analysis to male SLE patients should be done cautiously. To balance the sex ratio in
further studies may be beneficial to substantiate these findings. Finally, patients included
in this study had medical complications caused by SLE and also took several
medications, which may affect the prevalence of depression or anxiety. To apply those
findings to other SLE populations should again be a matter for caution.
In summary, depression and anxiety are highly prevalent in SLE patients. Anxiety and
young age are associated with depressive disorder in those patients. Therefore, routine
screening for the predictors for those patients in clinical settings may be beneficial.
Go to:
Acknowledgments
We thank the following for his substantial help with this project: Professor Stephen D
Martin, MBBS, MRCPsych, MEWI, Brandon Lane Neuropsychiatry Clinic, Durham,
United Kingdom.
Go to:
Footnotes
Disclosure
The authors declare that they have no conflicts of interest in this work.
Go to:
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Jurnal 3
PLoS One. 2013; 8(5): e63795.
Published online 2013 May 23. doi: 10.1371/journal.pone.0063795
PMCID: PMC3662722
Validity of LupusQoL-China for the

Assessment of Health Related Quality
of Life in Chinese Patients with
Systemic Lupus Erythematosus
Su-li Wang,1 Bin Wu,2 Lin Leng,3 Richard Bucala,3 and Liang-jing Lu1,*
George C. Tsokos, Editor
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Abstract
Objectives
To adapt and assess the validity and reliability of LupusQoL for use in Chinese patients
with systemic lupus erythematosus (SLE).
Methods
Debriefing interviews of subjects with SLE guided the language modifications of the
tool. The process of adaptation proceeded according to the guideline and pre-testing
results of LupusQoL-China. 220 SLE patients completed LupusQoL-China and a generic
preference-based measurement of health EuroQoL scale (EQ-5D), and 20 patients
repeated them after 2 weeks. Internal consistency (ICR) and test-retest (TRT) reliability,
convergent and discriminant validity were examined. Factor analysis and Rasch analysis
were performed.
Results
The mean (SD) age of the 208 subjects with SLE was 33.93 (9.19) years. ICR and TRT
of the eight domains ranged from 0.811 to 0.965 and 0.836 to 0.974, respectively. The
LupusQoL-China domains demonstrated substantial evidence of construct validity when
compared with equivalent domains on the EQ-5D (physical health and usual activities r =
0.63, pain and pain/discomfort r = 0.778, emotional health and anxiety/depression r =
0.761, planning and usual activities r = 0.560). Most LupusQoL-China domains could
discriminate patients with varied disease activities and end-organ damage (according to
SELENA-SLEDAI and SLICC-DI). The principal component analysis revealed six
factors, and confirmatory factor analysis result of which is similar to eight factors model.
Conclusions
These results provide evidence that the LupusQoL-China is valid as a disease-specific
HRQoL assessment tool for Chinese patients with SLE.
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Introduction
Systemic lupus erythematosus (SLE) is a chronic progressive autoimmune disease, which
can affect any organ, including the skin, kidney, lung, brain, heart, and joints. In addition
to natural disease progression, the long-term administration of glucocorticoids and other
immunosuppressants may significantly impact patients' life quality. With progress in
medical care, the 5-year survival rate for patients with SLE currently exceeds 90% [1]
[3]. A comprehensive objective assessment of the long-term outcomes of patients with
SLE, including disease activity, accumulated tissue damage, and health-related quality of
life (HRQoL) is desirable. A HRQoL assessment that evaluates patients health status and
personal sense of well being may more accurately reflect the burden of SLE disease
among patients. Therefore accurate HRQoL assessment of patients with SLE is desirable
and draws increasingly attention.
Its known that HRQoL among patients with SLE is worse than the general population,
particularly those fall victim at an earlier age [4]. Prior studies of HRQoL in SLE have
employed generic tools, such as the Short Form-36 (SF-36) [5], EuroQoL scale (EQ-5D)
[6], or 20-Item Short Form Health Survey (SF-20) [7], however it was found that generic
tools were not sensitive enough, and lacked of specific domains and items for SLE.
Therefore, attention has been turned toward developing a more disease-specific

questionnaire. LupusQoL, a new SLE-specific HRQoL measure, have been demonstrated
to be applicable to SLE patients in the UK and USA [8], [9]. To our knowledge, no SLEspecific HRQoL tools have been validated in Mainland Chinese. According to official
website of LupusQoL(http://lupusqol.com/), a Chinese version(Traditional Chinese) has
been applied to application in Taiwan. Although the language is similar, there are
meaningful differences between China Mainland and Taiwan in culture, economics,
education, religion, medical environment, and healthcare systems. Due to higher levels of
economic development and health administration, most SLE patients in Taiwan could
receive standardized treatment at an early stage, and the disease could be controlled at a
satisfactory level for a long time [10]. For this reason, HRQoL of SLE Taiwanese in
physical, functional and social domains could be relatively better than Mainlanders.
Therefore, the HRQoL of SLE patients in Mainland China may benefit from specific
differences from Taiwan. Our objective was to cross-culturally adapt the LupusQoL to
Mainland Chinese, and evaluate its measurement properties.
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Patients and Methods

Demographic Data
This study was approved by the institutional review board of Shanghai Jiaotong
University, and all subjects consented to participation. We included consecutive SLE
patients (n = 220) who had been followed up at Ren Ji Hospital, School of Medicine,
Shanghai Jiao Tong University from March to November of 2012. The inclusion criteria
were as follows: age between 18 and 75 years, and diagnosis of SLE according to the
1997 modified ACR criteria [11]. Demographic information included sex, age, age at
disease diagnosis, education and marital status.
LupusQoL
LupusQoL is a lupus-specific HRQOL questionnaire consisting of 34 items grouped in
eight domains: physical health (PH), pain (PN), planning (PL), intimate relationships
(IR), burden to others (BU), emotional health (EH), body image (BI) and fatigue (F) [8].
It has a five-point Likert response format, where 4 = never, 3 = occasionally, 2 = a good
bit of the time, 1 = most of the time, and 0 = all of the time. Modifications made between
the Taiwanese and Mainland Chinese version of LupusQol are described in the Results.
Summary scores for LupusQoL-China were calculated guided by the scoring guidelines
for LupusQoL-UK [8].
EuroQoL Scale (EQ-5D)

The EQ-5D is a generic preference-based measurement of health [[12]. It includes a
health state classifier that consists of five dimensions: mobility, self-care, usual activities,
pain/discomfort and anxiety/depression. A utility index-based summary score is derived
from the self-classifier, where 1 represents full health and 0 represents dead. Scores for
the five domains of the EQ-5D were generated.
Disease Characteristics
Disease activity was determined using the SLE Disease Activity Index (SLEDAI)
instrument [13]. The SLEDAI is a 24-item instrument for assessing SLE activity in nine
organ systems. Clinical and laboratory data are required to complete the questionnaire.
The score ranges from 0 to 105 points, with higher values signifying greater disease
activity. Damage was assessed using the SLE damage index (SLICC-ACR) tool [14].
SLICC/ACR-DI tracks irreversible organ dysfunction across 12 systems. The dysfunction
must be present for 6 consecutive months in order to register as damage. The score ranges
from 0 to 46, with higher scores signifying more damage.
Statistical Analyses
We used SPSS software, version 10.0 to analyze data. Descriptive statistics were
reported. The continuous variables were tested for normality; a non-parametric test
(Mann-Whitney) was used for comparing continuous data.
Content Validity
As LupusQoL was modified from a pre-existing Taiwan version, it was assumed that it
had a good content validity. We asked the pre-test sample of patients whether the items
were understandable, and made minor changes to the expression according the feedback.
Internal Consistency Reliability

Cronbachs was used to test for internal consistency, and was considered satisfactory
when 0.7 [15].
Test-retest Reliability
Test-retest reliability was determined using an intraclass coefficient to assess the stability
of the measure, comparing LupusQoL-China domains scores at baseline and 2 weeks
later in patients (n = 20) whose self-assessed quality of life was rated as no change on a
15-point health status change scale (7 to +7).
Discriminant Validity
Discriminant validity is used to assess whether the instrument can distinguish between
patients of different disease severity. There is not a validated instrument for severity of
SLE, so we used both disease activity and damage to define disease severity, which were
determined by SLEDAI and SLICC-DI. It was hypothesized that LupusQoL domains
would be significantly altered in patients with a SELENA-SLEDAI score cutoff of 4 or
SLICC-DI score cutoff of 1. And then discriminant construct validity using MannWhitney non-parametric tests was accessed.
Convergent Validity
We measured the extent of correlation between observed relationships of the concepts
and the hypothesized concepts to assess its convergent validity. A strong correlation was
defined as 0.70, moderate to substantial as 0.300.70 and weak as <0.30.
Factor Analysis
We conducted an exploratory factor analysis (EFA) [principal component analysis (PFA)
followed by varimax rotation] with 8 imposed factor loadings consistent with the UK
model to confirm its factor structure [9]. We next studied item loading on each factor
after rotation, considering 0.5 as significant loading. We computed an eight-factor item
loading matrix, according to the priori hypothesis of an eight-factor structure supported
by the original LupusQoL dimensionality. We used Kaisers criterion (eigenvalues>1),
Horns parallel analysis and graphical analysis of the screeplot to generate hypotheses
about the number of factors to be extracted [16], [17].
Then we performed a confirmatory factor analysis (CFA) using the UK structure of the
LupusQoL on AMOS software. In this analysis, each item was defined to represent only
one domain, but the domains were allowed to correlate with each other.
A separate exploratory factor analysis (EFA) without an imposed number of domains was
also performed and the model obtained was then tested by CFA.
Rasch Analysis
Rasch analysis is the standard for the development of metric quality outcomes in
healthcare [18]. We used Rasch analysis for each domain item, and obtained person and
item reliability index. Misfit item was defined by the absolute value of mean square
outfits >2 or <0.6 [9].
A two-tailed p value of 0.05 was considered significant in all analyses.
Go to:
Results
We first translated the traditional Chinese language of the Taiwan version of LupusQoL
into simplified Chinese. Two experts (a rheumatologist and one Chinese linguist) made
the draft versions independently. Then a multidisciplinary consensus committee was held
to discuss about the availability of an agreed-on version according to the consensus of the
two translators. During this meeting, the working group believed that this version was
perfectly understandable and conceptual equivalence of the source. We piloted a

simplified Chinese version of LupusQoL in 6 randomly selected outpatients with SLE.
Feedback was sought and discussed within our working group, with the result that
additional minor wording revisions were introduced; these did not result in any changes
in the original meaning. The main modification was in the examples provided in the
questionnaire; for instance, digging the garden, painting was replaced by carry gas
canister, rice bag for item 1 and dusting was replaced by sweeping for item 3. The
expression of quality used zhiliang instead of pinzhi. An additional 6 outpatients
completed this modified version and no further suggestions were offered to us. This
modified instrument, referred to as the LupusQoL-China, was the administered to our
recruited study patients.
Among 220 SLE patients included in the study, complete data was obtained from 208.
93.8% (n = 195) were women; all were Mainland Chinese. The mean (SD) age was 33.9
(9.19) years. The mean (SD) SLEDAI and SDI were 2.73 (3.91) (median 2, range 0
25) and 0.37 (0.869) (median 0, range 06), respectively.
The internal consistency reliability of the LupusQoL-China ranged from 0.811 to 0.965
(Table 1). The test-retest reliability ranged from 0.836 to 0.974 (Table 1). The LupusQoLChina domains had good construct validity when compared with equivalent domains on
the EQ-5D (Table 2).
Table 1
Reliability of LupusQoL used in Chinese patients with SLE
(LupusQoL-China).
Table 2
Convergent validity of LupusQoL used in Chinese patients with SLE
(LupusQoL-China).
LupusQoL-China could discriminate patients with varied disease activities in all domains
except for body image (Table 3). Similarly, it could differentiate subjects with varied
disease damages in all domains except burden to others and body image (Table 4).
Table 3
Discriminant validity of LupusQoL used in Chinese patients with SLE
(LupusQoL-China) with disease activity as the external anchor.
Table 4
Discriminant validity of LupusQoL used in Chinese patients with SLE
(LupusQoL-China) with damage as the external anchor.
Confirmatory factor analysis of the Chinese version of the LupusQoL using the eight
domain UK version loadings of the 34 items didnt resulted in a good fit (2/df 1.978, root
mean square error of approximation (RMSEA) 0.069, goodness-of-fit index (GFI) 0.821,
2 = 856.49, p = 0.001). Standardized regression weights for all items with their respective
domains were >0.6, except item 1(0.54) and 33(0.57).
EFA (principal component analysis) with 8-factor imposition resulted in the finding that
planning, intimate relationship, burden to others emotional health, body image and
fatigue items loaded on six separate domains as expected (see Table S1). However, item 9
(pain domain) loaded on the physical health domain and the other two pain items (item
10, 11) loaded on the intimate relationship factor domain. The last item of physical health
domain (item 8) loaded on one single factor. 6 of the 8 factors had an eigenvalue of >1
and cumulatively explained 74.3% of the variance. In 8 factors of the EFA result, the first
factor had an eigenvalue of 14.7 and explained 43.4% of the variance. Furthermore,
parallel analysis led to the retention of an 8-factor structure. Screeplot analysis suggested
a 6-factor loading structure (see Table S2). Physical health and pain (item 111)
composed the first factor. Intimate relationship and burden to others (item 1519)
constituted the same factor. Planning, emotional health, body image and fatigue had
separate factor loadings. The ICR of modified six domains were as follows: first factor
(physical health, pain; ICR = 0.94), second factor (planning; ICR = 0.92), third factor
(intimate relationship and burden to others; ICR = 0.91), fourth factor (emotional health;
ICR = 0.96), fifth factor (body image; ICR = 0.86) and sixth factor (fatigue; ICR = 0.86).
The six-factor model showed similar fit statistics in confirmatory factor analysis (2
876.05, p = 0.001, 2/df 2.2, RMSEA 0.077, GFI 0.89).
For Rasch analyses, results in fit analyses of items within each domain were acceptable
(mean square outfits were all >0.6 and none was >2 (Table 5). Item reliability of the pain
domain was poor. Person reliability of the pain and intimate relationship domain were
unsatisfactory.
Table 5
MNSQ values, item and person reliability indices of LupusQoL used in
Chinese patients with SLE (LupusQoL-China).
Go to:
Discussion
Systemic lupus erythematosus, an autoimmune illness with a wide spectrum of
manifestations, affects multiple organ systems and is associated with considerable
morbidity and mortality. The incidence of SLE appears to be higher in China compared to
America and Europe, and millions of Chinese patients are suffering from this disease
[19][21]. Due to deeper understanding of the disease itself and its management, the
disease is becoming chronic and controllable. However, because it is incurable and runs a
variable course over the patients remaining years, SLE still profoundly affects health
status, especially the HRQoL[22][24]. To our knowledge, there has been no SLEspecific HRQoL tools that have been validated for use among Mainland Chinese patients.
Meanwhile, generic tools were not designed for SLE population, so they may contain
irrelevant items and/or lack items deemed important to these patients, and may be less
sensitive than a disease-specific measure [25], [26]. Accordingly, it is desirable to find an
SLE-specific HRQoL tool validated for use in Chinese patients.
We modified the LupusQoL-Taiwan instrument to evaluate in Mainland Chinese patients,
and assessed its measurement properties. Because there are no published data about
validity and reliability of LupusQoL-Taiwan published, we compared our results with the
original version (LupusQoL-UK) and LupusQoL-USA in our study [8], [9].
Our results provide evidence that the LupusQoL-China is a valid tool to assess the quality
of life of SLE patients, and it is the first proposed SLE-specific HRQoL tool that may be
applied to all Chinese patients.
The ICR estimates of the LupusQoL-China were similar to those of the LupusQoL-UK.
The convergent and discriminant validity of the tool were good. In our data, the domain
of intimate relationship which reflects sexual health can also differentiate between
disease severity as well as other domains. We suggest that this result may be related to the
Chinese attitude toward sexual intercourse. Traditional concepts in Chinese culture

consider intercourse to be detrimental to health. When Chinese patients become ill, they
tend to repress sexual desires and choose to compromise their sex life, especially in cases
of severe disease.
Our exploratory factor analysis without constraining factor numbers showed a 6-factor
loading model; however, the results of ICR and confirmatory factor analysis changed
little. According to the description of items, we believe the original 8-factor model fits
better.
To ensure the validity of test-retest reliability, we choose two weeks as the time interval
between two tests, which is one week longer than in the original version of LupusQoL.
This duration (two weeks) was selected because it was sufficiently long enough for
patients to forget their original responses and short enough for the disease state to remain
unchanged [27]. The Rasch model analysis also suggested that the LupusQoL was wellunderstood for our patient cohort.
Its important to note that because the generation phase of items was conducted in the
UK, which included predominantly Caucasian patients, the characteristics of Chinese
patients with SLE may not be reflected completely. In addition, the difference between
two country in socioeconomic status and medical care services, which may impact health
status, may counter the face validity of the tool when used among Chinese SLE patients
[28].
Conclusions
In summary, our research provides evidence of validity and reliability of the modified
LupusQoL version (LupusQoL-China) among Mainland Chinese patients with SLE.
Additional larger studies are still required to further assess the psychometric properties
and optimal factor structure, and resolve its role in clinical trials and routine practice. We
hope that this study will prompt further attention to measurement of HRQoL in SLE
patients, which will ultimately lead to more efficient clinical management of SLE
population.
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Supporting Information
Table S1
Exploratory Factor Analysis with 8 factor constraints. Extraction Method: Principal
Component Analysis. Rotation Method: Varimax with Kaiser Normalization.
(DOC)
Click here for additional data file.(65K, doc)
Table S2
Exploratory Factor Analysis without constraints. Extraction Method: Principal
Component Analysis. 6 factors have been extracted.
(DOCX)
Click here for additional data file.(16K, docx)
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Acknowledgments
We gratefully acknowledge Dr. Lee-Suan Teh, Mary Gawlicki, East Lancashire Hospitals
NHS Trust and Translation Corporation Inc for providing us the LupusQoL(Chinese
Traditional). We also gratefully acknowledge the EuroQol Group for kindly providing
EQ-5D (5L) to us.
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Funding Statement
This work was supported by grants from the National Natural Science
Foundation of China (No.81072469; No.30671946) and Shanghai Natural
Science Foundation (No.09ZR1417600). The funders had no role in study
design, data collection and analysis, decision to publish, or preparation of the
manuscript.
Go to:
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Jurnal 4
BMC Med. 2013; 11: 91.
Published online 2013 April 4. doi: 10.1186/1741-7015-11-91
PMCID: PMC3616809
Discoveries in the pathophysiology of

neuropsychiatric lupus erythematosus:
consequences for therapy
Takahisa Gono, 1 Yasushi Kawaguchi,1 and Hisashi Yamanaka1
This article has been cited by other articles in PMC.
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Abstract
Systemic lupus erythematosus (SLE) is a multi-system inflammatory disorder

characterized by the presence of several autoantibodies, including anti-double-stranded
DNA. Neuropsychiatric (NP)LE contributes to the prognosis of SLE, and is divided into
19 NPLE syndromes. Its mechanisms are mediated through autoantibodies, complement
components, and cytokines. The pathophysiology and diagnosis of NPLE are diverse and
complicated. Recent studies have shown that several autoantibodies cross-react with
human brain tissue and cause NPLE symptoms in SLE. It is known that in mice,
depression and hippocampus-related memory impairment are induced by anti-ribosomal
P antibody and anti-NR2 antibody, respectively. In a BMC Medicine research article,
Kivity et al. demonstrated novel work showed that the 16/6 Id antibody impaired visual
memory and spatial memory by causing hippocampal injury in mice. Given differences in
the cross-reactivity of each autoantibody with the nervous system, the clinical features
might be different and diverse in NPLE. Identification of autoantibody targets could lead
to the development of novel therapies. Investigators and clinicians should consider not
only the inhibition of autoantibody synthesis but also the protection of neuronal cells in
the treatment strategy for NPLE.
See related Research article: http://www.biomedcentral.com/1741-7015/11/90
Keywords: Systemic lupus erythematosus, Autoantibody, Cross-reactivity,
Neuropsychiatric symptoms
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Introduction
Systemic lupus erythematosus (SLE) is a multi-system inflammatory disorder
characterized by the presence of autoantibodies directed against double-stranded (ds)
DNA. The prevalence ranges from 20 to 150 cases per 100,000 population, and it seems
to be increasing, partly because the disease is recognized more readily and partly because
of longer survival [1]. Specifically, lupus nephritis, which is a kidney disorder that is a
complication of SLE, and neuropsychiatric (NP)LE contribute to the prognosis of SLE.
NPLE is classified by the American College of Rheumatology (ACR) into 19
neuropsychiatric syndromes [2]. The diffuse central nervous system (CNS) form, focal
CNS form, and peripheral nervous system (PNS) form were defined as diffuse
psychiatric/neuropsychological syndromes, neurologic syndromes, and PNS syndromes,
respectively, by the ACR. The pathophysiology of NPLE is mediated by several factors,
including vasculitis, thromboembolism, and inflammation and apoptosis of neuronal and
glial cells. Its mechanisms are mediated through autoantibodies, complement
components, cytokines, chemical mediators, and inflammatory cells, including
neutrophils, lymphocytes, and plasma cells. Thus, the pathophysiology and diagnosis of
NPLE are diverse and complicated, which makes therapy difficult. The diagnosis of
NPLE is based on the results of several investigations, including neurological
examination, brain/spinal cord magnetic resonance imaging, electroencephalography,
cerebrospinal fluid analysis, nerve-conduction studies, psychiatric interview, and a short
battery of neuropsychological tests recommended by the ACR committee [2].
Recent novel studies have identified some aspects of the pathophysiology of NPLE.
Some anti-dsDNA antibodies cross-react with the N-methyl-D-aspartate (NMDA)
receptor subunit 2 (NR2) in SLE [3]. NMDA receptors are ligand-gated ion channels that
play crucial roles in synaptic transmission and CNS plasticity. NMDA receptor
dysfunction has been implicated in multiple brain disorders, including stroke, chronic
neurodegeneration, epilepsy, and schizophrenia. Anti-NR2 antibodies breaching the
bloodbrain barrier (BBB) can cause neuronal damage via an apoptotic pathway [4,5].
The 16/6 idiotype (Id) antibody, which was the focus of a recent study by Kivity et al. [6],
is considered to be an anti-dsDNA Id antibody in SLE. Immunization of naive mice with
the human 16/6 Id monoclonal antibody induced an SLE-like disease characterized by
serological, clinical, and pathological features. This antibody cross-reacts with
cytoskeletal proteins, glycoproteins, and brain glycolipids, as well as with pathogens such
as Mycobacterium tuberculosis[7]. Deposition of 16/6 Id antibodies has been found in
human tissues, such as the skin, kidney, and brain [8], and levels are high in patients with
active SLE or NPLE [9]. These findings indicate that the 16/6 Id antibody is potentially
one of the factors that cause NPLE. However, the way in which these neuropsychiatric
symptoms are induced by the 16/6 Id antibody reaching the CNS and the underlying
mechanisms of this induction are unknown. In their study, Kivity et al. showed for the
first time the effect of the 16/6 Id antibody on the CNS by injecting naive mice
intracerebroventricularly with the 16/6 Id antibody [6]. In this commentary, we discuss
their results and the pathophysiology and treatment strategy for NPLE.
Neurological effects of the 16/6 Id antibody

To understand if the 16/6 Id IgG antibody is able to induce neurological effects, Kivity et
al. compared the cognitive and behavioral performance of C3H female mice that had
been injected with the human 16/6 Id IgG antibody (16/6 Id mice subset) and those
injected with a commercial human IgG (control mice subset) [6]. Visual-recognition
memory was assessed by using the novel-object recognition test. The authors found that
there was a significant preference for attention to the new object compared with the old
object by the control mice, but no difference in preference was found between the new
and the old objects by the 16/6 Id mice. This result indicates impairment of visualrecognition memory in the 16/6 Id mice. In the Y-maze test, which assesses spatial
memory, the 16/6 Id mice were also found to have impairment of spatial memory.
In addition, the brain pathology of these mice was examined to establish the potential
mechanism by which the 16/6 Id IgG antibody is able to exert its neurological effects. In
the brain tissue, increased microglial activation was seen in the hippocampus and
amygdala, but not in the neurocortex or piriform cortex. In addition, the number of
astrocytes in the hippocampus was found to be increased. Taken together, these results
show that in mice, the 16/6 Id antibody causes impairment of both visual and spatial
memory through hippocampal injury, and might selectively cross-react with some
antigens in the hippocampus.
The 16/6 Id antibody is a novel antibody contributing to the

pathophysiology of NPLE
Kivity et al. also showed that, in addition to the anti-ribosomal P and anti-NR2
antibodies, another autoantibody, anti-16/6 Id antibody, can cross-react with human brain
tissue and cause NPLE symptoms in SLE [6]. Brain tissue-reactive antibodies in NPLE
are thought to be synthesized in the CNS or peripheral organs, such as the lymph nodes
and bone marrow [10]. Therefore, if NPLE is associated with antibodies reaching the
CNS through the BBB, treatments that not only eliminate brain-tissue-reactive antibodies
but also protect the integrity of the BBB should be considered.
Therapy of NPLE is currently difficult. Although corticosteroids and immunosuppressive
agents, such as cyclophosphamide, are broadly effective for NPLE, the condition is
occasionally refractory to these treatments. Moreover, brain-tissue-reactive
autoantibodies might cause irreversible neuronal degeneration via apoptosis. For
instance, anti-ribosomal P antibody targets a neuronal surface protein, causing calcium
influx and apoptosis [11]. These antibodies specifically bind to neurons in the
hippocampus, cingulate cortex, and the primary olfactory piriform cortex, and, in mice,
resulted in the induction of depression. These results implicate the olfactory and limbic
areas in the pathogenesis of depression in SLE [12]. The anti-NR2 antibody also causes
neuronal cell apoptosis, impairs the hippocampus-dependent memory function in mice,
stimulates NMDA receptor-mediated synaptic responses and excitotoxicity through
enhanced mitochondrial permeability [13]. and decreases cell viability through increased
Ca2+ influx [5]. Kivity et al. showed that the anti-16/6 Id antibody hampers visualrecognition and spatial memory. Their hypothesis about the pathophysiology of anti-16/6
Id antibody-induced brain involvement was that brain inflammation induces modification
of neuronal function and neuronal degeneration [6]. The authors also found increases in
astrocyte number and microglial activation in the hippocampus of anti-16/6 Id antibodyinjected mice. They suggested that increased astrocytes and activated microglial cells
were involved in brain inflammation and therefore, an inflammatory process may affect
cognitive impairment in mice injected with anti-16/6 Id antibody. By contrast, there was
minimal local activation of astrocytes and microglial cells, and no lymphocytic
inflammation in the brains of anti-NR2 antibody-injected mice [3].
It is plausible, therefore, that the wide variety of NPLE syndromes might be caused by
differences in the recognition of brain tissue by lupus autoantibodies, such as antiribosomal P, anti-NR2, and anti-16/6 Id antibodies. Identification and evaluation of such
differences would perhaps be useful in developing therapies for NPLE.
Future directions and conclusions

In the future, it is hoped that new agents will be developed to improve the prognosis for
NPLE. The efficacy of such new agents should be determined through their ability to
protect neuronal cells, modulate intracellular Ca2+, or regulate the deposition of
autoantibodies in NPLE. Memantine is a drug used to treat Alzheimers disease, which
modulates intracellular Ca2+ by blocking NMDA receptors. In addition, the DWEYS
pentapeptide, which the anti-NR2 antibody recognizes as an antigen, prevents the antiNR2 antibody from being deposited in tissues and mediating neuronal excitotoxicity in
mice [14].
As Kivity et al. have shown, several autoantibodies against brain tissue are involved in
NPLE. Given the differences in the cross-reactivity of each autoantibody with the
nervous system, this may explain the difference and diversity of the clinical features in
NPLE. Investigators and clinicians should consider not only inhibition of autoantibody
synthesis but also protection of neuronal cells when investigating treatment strategies for
NPLE.
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Abbreviations
ACR: American college of rheumatology; BBB: Bloodbrain barrier; CNS: Central
nervous system; ds: Double-stranded; NMDA: N-methyl-D-aspartate; NPLE:
Neuropsychiatric lupus erythematosus; PNS: Peripheral nervous system; SLE: Systemic
lupus erythematosus
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Competing interests
The authors declared that they have no competing interest.
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Authors contributions
TG drafted the manuscript, and YK and HY read and revised it. All authors have given
final approval of the final manuscript to be published.
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Authors information
TG is an assistant professor in the Institute of Rheumatology (IOR), Tokyo Womens
Medical University (TWMU), and is interested in the neurological complications
associated with connective tissue disease. YK is an associate professor of Medicine and
Rheumatology in TWMU. HY is a professor of Medicine and Rheumatology, and a
director of the IOR, TWMU. All authors are board-certified members of the Japan
College of Rheumatology.
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Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1741-7015/11/91/prepub
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lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in
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Katsumata Y, Yoneda Y, Yamanaka H. NR2-reactive antibody decreases cell
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Blank M, Anaya JM, Mozes E, Chapman J, Shoenfeld Y. 16/6-Idiotype expressing
antibodies induce brain inflammation and cognitive impairment in mice: the
mosaic of central nervous system involvement in lupus. BMC Med. 2013. [PMC
7. Andr-Schwartz J, Datta SK, Shoenfeld Y, Isenberg DA, Stollar BD, Schwartz
RS. Binding of cytoskeletal proteins by monoclonal anti-DNA lupus
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8. Isenberg DA, Collins C. Detection of cross-reactive anti-DNA antibody idiotypes
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Schwartz RS. Anti-DNA antibody idiotypes in systemic lupus erythematosus.
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10. Sencal JL, Raymond Y. The pathogenesis of neuropsychiatric manifestations in

systemic lupus erythematosus: a disease in search of autoantibodies, or
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11. Matus S, Burgos PV, Bravo-Zehnder M, Kraft R, Porras OH, Faras P, Barros LF,
Torrealba F, Massardo L, Jacobelli S, Gonzlez A. Antiribosomal-P autoantibodies
from psychiatric lupus target a novel neuronal surface protein causing calcium
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12. Katzav A, Solodeev I, Brodsky O, Chapman J, Pick CG, Blank M, Zhang W,
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Jurnal 5
J Rheumatol. Author manuscript; available in PMC 2013 April 22.

Published in final edited form as:
J Rheumatol. 2012 February; 39(2): 262268.
Published online 2011 December 15. doi: 10.3899/jrheum.110327
PMCID: PMC3632335
NIHMSID: NIHMS457765
Association Between Depression and

Vascular Disease in Systemic Lupus
Erythematosus
CAROL M. GRECO, PhD, TRACY LI, PhD, ABDUS SATTAR, PhD, AMY H. KAO,
MD, MPH, NATALYA DANCHENKO, PhD, DANIEL EDMUNDOWICZ, MS, MD,
KIM SUTTON-TYRRELL, DrPH, RUSSELL P. TRACY, PhD, LEWIS H. KULLER,
MD, DrPH, and SUSAN MANZI, MD, MPH

The publisher's final edited version of this article is available at J Rheumatol
See other articles in PMC that cite the published article.
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Abstract
Objective
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with
increased prevalence of cardiovascular disease (CVD) and depression. Although
depression may contribute to CVD risk in population-based studies, its influence on
cardiovascular morbidity in SLE has not been evaluated. We evaluated the association
between depression and vascular disease in SLE.
Methods
A cross-sectional study was conducted from 20022005 in 161 women with SLE and
without CVD. The primary outcome measure was a composite vascular disease marker
consisting of the presence of coronary artery calcium and/or carotid artery plaque.
Results
In total, 101 women met criteria for vascular disease. In unadjusted analyses, several
traditional cardiovascular risk factors, inflammatory markers, adiposity, SLE diseaserelated factors, and depression were associated with vascular disease. In the final
multivariable model, the psychological variable depression was associated with nearly 4fold higher odds for vascular disease (OR 3.85, 95% CI 1.37, 10.87) when adjusted for
other risk factors of age, lower education level, hypertensive status, waist-hip ratio, and
C-reactive protein.
Conclusion
In SLE, depression is independently associated with vascular disease, along with physical
factors.
Key Indexing Terms: SYSTEMIC LUPUS ERYTHEMATOSUS, CARDIOVASCULAR
DISEASE, DEPRESSION CALCIFICATION, CAROTID PLAQUE, PSYCHOSOCIAL
FACTORS
Depression and cardiovascular disease (CVD) are among the most prevalent and
disabling conditions worldwide, contributing to the global public health burden1. Patients
diagnosed with heart disease are at increased risk for developing depression up to 8 years
after medical diagnosis2. In populations initially free of cardiac disease, depression
increases risk for subclinical atherosclerosis by greater than 2-fold3,4, and risk for incident
cardiac events by 50% or more5,6, including a 4.5-fold increased risk for myocardial
infarction (MI)7. In patients with existing CVD, the presence of depression increases the
risk of future cardiac events8, and increases risk of mortality up to 5 years following first
MI9.
Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory autoimmune
disease characterized by high rates of both CVD and depression. Young female patients
with SLE have a 50-fold increased risk of MI compared to women without lupus10, and
higher than expected rates of stroke and hypertension11. Markers of subclinical
atherosclerosis, such as coronary artery calcium (CAC) and carotid plaque, are also more
prevalent in women with SLE12,13. These atherosclerotic markers predict future cardiac
events in SLE14 and therefore serve as surrogates for CVD. Notably, although all-cause
mortality rates in patients with SLE have decreased in recent decades, CVD-related
mortality has not15. Thus, understanding and treating the risk factors for CVD in SLE is
important.
Investigations have shown that traditional CV risk factors such as hypertension,
hyperlipidemia, and high body mass index (BMI)16,17,18 are associated with increased rates
of atherosclerotic changes in SLE. However, the presence of traditional risk factors alone
does not fully explain the greatly increased risk for CVD in SLE.
In addition to traditional CVD risk factors, it has been clearly shown that a lupus factor
related to SLE disease or its treatment is an important contributor to atherosclerotic
changes and CVD in SLE19,20. Longterm use of cortico-steroids, high levels of
inflammation, and accrued organ damage due to immune activation are some of the
potential lupus factor candidates contributing to CVD in this group.
Depression may play a role in lupus as well as in CVD. Depression is more prevalent in
patients with SLE than in controls and in patients with other inflammatory conditions
such as rheumatoid arthritis and ankylosing spondylitis21,22,23. There is some evidence that
depression is associated with SLE disease activity22,23,24. Depression is associated with
poor medication adherence among SLE patients25 as well as cognitive impairment26,27.
Although studies of CVD in SLE frequently include disease-related variables, the
potential role of depression has received little attention.
We evaluated psychological as well as biological factors associated with atherosclerosis
in SLE, a chronic inflammatory disease with high rates of CVD, mental health concerns,
and traditional biological and demographic patterns commonly associated with poor heart
health.
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MATERIALS AND METHODS

Study population
The participants in this study were women with SLE enrolled in the Heart Effects on
Atherosclerosis and Risk of Thrombosis in SLE (HEARTS) investigation, funded by the
National Institutes of Health (R01 AR46588). The purpose of the HEARTS study was to
compare prevalence and risk factors for coronary artery calcification in women with SLE
and healthy controls. The participants had no history of CVD events28 and were
nonselectively recruited from the Pittsburgh Lupus Registry, which at the time of
enrollment included 983 living participants. The registry includes patients seen at
inpatient or outpatient facilities at the University of Pittsburgh Medical Center or by
practicing rheumatologists within the Pittsburgh metropolitan area. All women with SLE
were required to fulfill 1982 or 1997 American College of Rheumatology (ACR) revised
criteria for the classification of definite or probable SLE29,30 and be over the age of 18
years.
All participants completed informed consent procedures. The study was approved by the
University of Pittsburgh Institutional Review Board.
Procedures
The study procedures included an interview, completion of a validated depression
questionnaire [the Center for Epidemiologic Studies Depression Scale (CES-D)]31,
physical examination, and laboratory and imaging studies [electron beam computed
tomography (EBT) and carotid ultrasound]. Each participant completed the study
procedures during a single study visit. Data for this cross-sectional study were collected
between March 2002 and September 2005.
Traditional cardiovascular risk factors

Information was collected on age, patient-reported race, education level, smoking habits,
family history of CVD (MI, stroke, or sudden death of a first-degree relative before age
60 yrs), waist and hip circumference, and BMI. Blood pressure was determined and
hypertension was defined as blood pressure > 140 mm Hg systolic or > 90 mm Hg
diastolic or the use of antihypertensive therapy. Fasting blood samples were obtained for
standard laboratory testing of total cholesterol, low-density lipoprotein cholesterol, highdensity lipoprotein cholesterol, triglycerides, insulin, albumin, homocysteine, and glucose
levels. Insulin resistance was calculated using the homeostatic model formula32,33: [insulin
(mU/l) glucose (nmole/l)]/22.5.
Inflammatory markers
Laboratory assessments of inflammatory markers were conducted using blood samples
from the single study visit. Assays were run in batches to reduce analytical variability.
Soluble E-selectin (sE-selectin) and soluble intercellular adhesion molecule-1 (sICAM-1)
were measured by commercial assays (Parameter Human sE-Selectin Immunoassay and
Human sICAM-1 Immunoassay; both from R&D Systems, Minneapolis, MN, USA).
High sensitivity C-reactive protein (hsCRP) was quantified by automated particleenhanced immunonephelometry (BN-II, Siemens Healthcare Diagnostics, Deerfield, IL,
USA). Fibrinogen was measured using an automated clot-rate assay (Diagnostica Stago
STA-R, Parsippany, NJ, USA)34,35 (R.P. Tracy, University of Vermont).
SLE-related factors
Rheumatologists specializing in SLE (AHK, SM) assessed disease activity and
cumulative organ damage due to SLE at the study visit. Measures included the revised
Systemic Lupus Activity Measure (SLAM-R)36 and the SLE Disease Activity Index
(SLEDAI)37. The SLAM-R assesses disease activity in 11 organ systems occurring over
the previous month, with possible score range 081. The SLEDAI contains weighted
descriptors of SLE signs and symptoms present in the past 10 days, and the score can
range from 0 to 105. Organ damage due to SLE was measured using the Systemic Lupus
International Collaborating Clinics (SLICC) damage index38 with the vascular items
removed, yielding a possible score range of 036. We also collected information
regarding individual criteria for SLE diagnosis and history of steroid use.
Psychosocial assessment
Participants completed the CES-D during the study visit. The CES-D is a validated 20item self-report instrument used extensively in community samples and medically ill
groups, including SLE21,39,40,41. The CES-D items assess past-week symptoms, such as
persistent sadness, low motivation, and feelings of worthlessness, that are consistent with
a depressive disorder. Although the CES-D is not used to diagnose specific depressive
disorders, clinically significant depression is typically defined as a CES-D score > 1631,42.
We used a CES-D symptom score > 16 as the indicator of clinically significant
depression.
Vascular disease endpoint

The vascular disease indicator for the study was a composite consisting of presence of
CAC and/or carotid artery plaque. Such composites are accepted practice in
atherosclerosis and CV event research43,44. The first step in determining the composite
vascular disease indicator was to measure for the presence of CAC using EBT (Imatron
C-150 scanner; Imatron, San Francisco, CA, USA). Thirty to forty 3-mm slices starting at
the aortic root to the apex of the heart were scanned in all participants at the same point
during diastole (80% of the RR interval in the electrocardiogram) during a single breathhold. The images were scored for calcification using the Agatston method45. Presence of
CAC was defined as Agatston score > zero. For carotid artery plaque, the carotid
ultrasound methodology has been described16. A Toshiba SSA-270A scanner (Toshiba,
Tustin, CA, USA) equipped with a 5-MHZ linear array imaging probe was used to image
the carotid arteries. Sonographers scanned the right and left common carotid artery,
carotid bulb, and the first 1.5 cm of the internal and external carotid arteries. Plaque was
defined as a distinct area protruding into the vessel lumen that was at least 50% thicker
than the surrounding areas. For each area scanned, the degree of plaque was graded 0 (no
observable plaque) to 3 (plaque covering 50% of the vessel diameter); grades were
summed across the right and left carotid arteries to create an overall measure of focal
plaque extent, called the plaque index. The plaque index has been found to be a
reproducible and valid measure of carotid atherosclerosis in a number of populations46.
For the current study, the presence of carotid plaque was defined as plaque index 1.
Data analysis
We checked the quality of the data by evaluating the frequency distribution of all relevant
variables, and assessed for multicollinearity among the variables. Continuous variables
were summarized as mean (SD) and categorical variables as percentages (n). Continuous
variables that had skewed distribution, such as waist-hip ratio, were transformed into
quartiles. The primary outcome measure was a binary variable indicating vascular
disease, defined as presence of CAC and/or carotid artery plaque. Logistic regression was
used to evaluate the univariate associations between each of the traditional, inflammatory,
psychological, and SLE-related factors and the presence or absence of vascular disease.
Variables associated with vascular disease in the univariate analyses were considered for
inclusion in the multivariable logistic regression model, based on the variable selection
methodology described in Vittinghoff47. To select variables for inclusion in multivariable
models, we first chose those found to be significant (p < 0.15) in unadjusted single
predictor models. Each of these variables was evaluated systematically for inclusion in
the multivariable logistic regression model48, and was retained or removed based upon
Akaike information criteria (AIC). The systematic evaluation of variables for inclusion
was an iterative process. An example of the iterative process would be starting with
important variables such as age and hypertension in the model, inflammatory variables
may be added one by one, their significance assessed, and AIC evaluated to determine
which inflammatory marker or sets of inflammatory markers fits best in the model or
whether they should be removed. Then SLE variables would be considered, one by one,
in a similar fashion, and the model would be evaluated with and without the
inflammatory variable or variables. Variable inclusion and removal proceeds in this
fashion until all significant univariate variables have been considered. The adequacy of
the final multivariable model was evaluated using the specification link test and HosmerLemeshow goodness-of-fit test. SPSS 15 (SPSS Inc., Chicago, IL, USA) and Stata 9
(Intercooled Stata 9.1; StataCorp LP, College Station, TX, USA) were used to perform all
statistical analyses. The final model was checked for interaction effects.
Go to:
RESULTS
Clinical and demographic characteristics
One hundred sixty-one women with SLE were enrolled in the study and completed the
assessments. Overall mean age was 50.0 years (SD 10.0); 88% (SD 141) were white, and
55% (SD 89) were hypertensive (defined as using antihypertensive medication or having
blood pressure > 140/90 mm Hg). Total cholesterol was 190 mg/dl (SD 41) and waist-hip
ratio was 0.85 (SD 0.1). The mean CES-D score was 11.6 (SD 9), with 27% of the sample
(43/161 women) scoring at or above 16, a score consistent with clinically meaningful
depressive symptoms. Of a possible range of 060, the CES-D score ranged from 0 to 45
in the sample overall. We evaluated associations between depression and other
characteristics using logistic regression. Older age and being in the second quartile of
waist-hip ratio were marginally associated with depression (p = 0.056, p = 0.078,
respectively). Depression was not associated with hypertension, race, education,
cholesterol, and steroid use.
SLE characteristics
Disease-related characteristics of the SLE sample are provided in Table 1. The average
length of time from SLE diagnosis was 16.3 (SD 7.0) years (range 547 yrs). Current
SLE disease activity was mild, on average, with mean SLAM-R of 4.5 (SD 2.9, range 0
15), and mean SLEDAI was 2.0 (SD 2.3, range 114). Cumulative organ damage scores,
i.e., SLICC-ACR Damage Index without vascular items, averaged 1.4 (SD 1.6, range 0
9). Regarding treatment with steroids, the majority of patients (110 of 161) had used
steroids, with a median duration of 10 years of use.
Table 1
Characteristics of patients with systemic lupus erythematosus (SLE) (n = 161).
Vascular disease and CVD risk factors

Forty-eight percent (SD 77%) of patients showed evidence of CAC, and carotid plaque
was found in 36% (SD 58%). The calcium and plaque data are not shown in the tables.
One hundred one (63%) of the women showed evidence of vascular disease, defined as
presence of coronary calcium and/or carotid plaque. Demo-graphic characteristics and
CVD risk factors of SLE patients with and without evidence of vascular disease are
shown in Table 2. Several traditional CVD risk factors were associated with vascular
disease, including age, years of education, hypertension, adiposity, elevated triglyceride
levels, glucose, and insulin resistance. SLE patients with vascular disease had higher
mean waist-hip ratios compared to those without vascular disease (0.86 0.1 vs 0.82
0.1, respectively; p = 0.03). Further, those in the highest quartile of waist-hip ratio were
more likely to have vascular disease, with an unadjusted OR of 3.99 (95% CI 1.4610.88;
p = 0.007). Inflammatory factors related to vascular disease were higher levels of hsCRP,
sE-selectin, and fibrinogen. Depression, defined as CES-D depressive symptom score >
16, was more prevalent among SLE women with vascular disease (35%) compared to
those without (15%; p = 0.004). CES-D scores ranged from 0 to 45 in women with
vascular disease, and from 0 to 38 in those without. In terms of SLE disease
characteristics, women with SLE who had evidence of vascular disease had greater
cumulative damage due to SLE and longer history of corticosteroid use.
Table 2
Unadjusted logistic regression analysis of covariates of vascular disease in patients with
SLE. Covariates with p < 0.15 were evaluated for inclusion in multivariable models.
Statistically significant differences (p < 0.05) between SLE ...
The final multivariable model for presence of vascular disease in women with SLE
included several traditional cardiovascular risk factors (age, hypertension, years of
education), inflammation, adiposity, and depression (Table 3). Women in the highest
quartile of waist-hip ratio ( 0.87) were 4 times more likely to have vascular disease,
after adjustment for other risk factors. Patients with depression had nearly 4-fold
increased odds for vascular disease (OR 3.85, 95% CI 1.3710.87), independent of
traditional risk factors, adiposity, and CRP. Notably, the univariate OR and CI for
depression were relatively unchanged after adjustment for the other significant and
relevant covariates. This finding indicates that depression has an independent role in
CVD. The final model was also checked for interaction effects and there were none.
Table 3
Multivariable logistic regression analysis of risk factors for vascular disease in women
with SLE (n = 161).
Go to:
DISCUSSION
Our results indicate that both psychological and biological factors are associated with
vascular disease in women with SLE. Depression is strongly associated with vascular
disease, after adjusting for other traditional and inflammatory risk factors. There are
several potential pathways that link depression and CVD in SLE. These pathways include
possible biological mechanisms, and may also reflect behavioral and environmental
influences on health.
Depression is associated with increases in proinflammatory cytokines49,50 and the
increased CVD risk in depressed persons may be related to added inflammatory burden.
A recent case-control study found an elevation in the proinflammatory cytokine
interleukin 6 (IL-6) in SLE, and this inflammatory factor was associated with CAC20. The
association between depression and inflammation is likely bidirectional51. An
inflammatory environment, which is typically present in patients with SLE, may result in
low mood and malaise52.
Depressed mood, particularly when chronic, may have a negative influence on lifestyle
and behavior choices. For example, depression is a risk factor for poor medication
adherence in SLE25 and in adults with heart disease53. Depression may interact with
physical inactivity to influence CVD. Murine studies indicate that depressed behavior
induced by chronic intermittent stress led to reduced exercise and ultimately to early
atherosclerotic changes54. In a population study of elderly men, baseline depressive
symptoms were associated with physical inactivity. Ten-year risk of cardiac mortality was
increased about 50% by the combined effect of depressive symptoms with inactivity55.
We considered adiposity as a potential pathway linking depression and vascular disease.
Adiposity has received attention in CVD research because adipose tissue, particularly
visceral adipose tissue, is known to produce inflammatory factors. In a medically healthy
group, depression was found to influence weight accumulation, which led to increased
production of inflammatory cytokines56. In SLE, obesity was related to increased levels
of CRP and IL-6, as well as reduced functional capacity57. Our group recently found that
BMI mediated an association between depressive symptoms and CAC in SLE58.
However, in our current study we found that even after adjusting for waist-hip ratio, itself
an important risk factor, depression was strongly associated to vascular disease.
In SLE, depression can be a manifestation of central nervous system (CNS) involvement.
Although the classification criteria for SLE include only history of seizures or psychosis
as the indicators of neurologic involvement30, depression is a component of
neuropsychiatric lupus59. Mood disorders are included among the 19 central and
peripheral neuropsychiatric syndromes listed in the 1999 ACR nomenclature for
neuropsychiatric lupus60.
Whether depression is linked to CVD in SLE through behavioral pathways, biological
pathways, or both remains unresolved. Depression may result from the struggle to cope
with a fatiguing, painful, and unpredictable chronic condition. SLE frequently is
associated with work disability and loss of income, which could contribute to depression
as well as to reduced ability to access healthcare. Depression and low access to healthcare
may both contribute to low adherence with medical treatment, possibly resulting in
increased risk of CVD. On the other hand, depression may be a product of the
inflammatory milieu of SLE. To the extent that inflammation contributes not only to
CVD risk directly but also, on an individual level, to feelings of malaise and low
motivation, depression may be a direct consequence of inflammation. However,

depression may also add to inflammatory burden through increased sedentary behavior,
leading to increased adipose tissue, which is an additional source of inflammation. It is
likely that paths linking depression with CVD in SLE are multifactorial as well as
bidirectional, and further investigation of these issues is needed.
One limitation of our study is that we did not investigate precisely whether depressive
symptoms were directly related to SLE (e.g., a manifestation of CNS lupus) or indirectly
related, such as a psychosocial consequence of the life changes brought about by SLE.
The cross-sectional design is a limitation that restricts our ability to infer that depression
or other risk factors are causally related to vascular disease in SLE. Presumably, vascular
changes take place over a long time. Certain risk factors such as adiposity and
hypertension may be presumed to be longstanding, but current depressive symptoms may
be transient rather than chronic. The CES-D is widely used for quantifying depressive
symptoms, in SLE as well as other groups. However, we acknowledge that there are other
methods to assess depression, such as the Structured Clinical Interview for the
Diagnostic and Statistical Manual of Mental Disorders61. The addition of a diagnostic
interview would have the advantage of documenting clinical diagnosis as well as
chronicity of depression. Ideally, future studies of the biological and psychological risks
for CVD in SLE will include prospective data collection, mood disorder diagnosis in
addition to self-report symptoms, and more precise investigation into possible
mechanisms linking depression and CVD.
Depression may be associated with premature atherosclerotic disease in SLE through
behavioral or biological pathways, or both. In women with SLE, depression is prevalent
and is an important influence on physical health and comorbidity in addition to its effect
on quality of life. Depression is treatable pharmacologically and through psychotherapy.
Attention should be paid to diagnosing and treating depression in SLE, as this should not
only contribute to improved quality of life, but possibly improve adherence to medical
regimens and physical activity recommendations. Thus, improving management of
depression may directly or indirectly influence physical health and overall CVD risk in
patients with SLE.
Go to:
Acknowledgments
Supported by the National Institutes of Health National Institute of Arthritis,
Musculoskeletal and Skin Diseases (K23 AR051314, R01 AR46588-01, K24 AR0221301, K23 AR051044); National Center for Research Resources/General Clinical Research
Center (M01 RR000056); American College of Rheumatology Research and Education
Foundation (Health Professional Investigator Award, Physician Scientist Development
Award); and Bristol-Myers Squibb.
Go to:
Footnotes
C.M. Greco, PhD, Department of Psychiatry, University of Pittsburgh School of
Medicine; T. Li, PhD, Global Epidemiology and Outcomes Research, Bristol-Myers
Squibb; A. Sattar, PhD, Department of Epidemiology and Biostatistics, Case Western
Reserve University School of Medicine; A.H. Kao, MD, MPH, Department of Medicine,
West Penn Allegheny Health System; N. Danchenko, PhD, Lundbeck SAS; D.
Edmundowicz, MS, MD, University of Pittsburgh Cardiovascular Institute; K. SuttonTyrrell, DrPH, Department of Epidemiology and Biostatistics, Case Western Reserve
University School of Medicine; R.P. Tracy, PhD, University of Vermont; L.H. Kuller,
MD, DrPH, Department of Epidemiology and Biostatistics, Case Western Reserve
University School of Medicine; S. Manzi, MD, MPH, Department of Medicine, West
Penn Allegheny Health System.
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Jurnal 6
Arthritis Care Res (Hoboken). Author manuscript; available in PMC 2013 July 9.
Arthritis Care Res (Hoboken). 2012 March; 64(3): 448454.
doi: 10.1002/acr.21566
PMCID: PMC3705711
Validity of Brief Screening Tools for

Cognitive Impairment in Rheumatoid
Arthritis and Systemic Lupus
Erythematosus
LAURA J. JULIAN, PhD, JINOOS YAZDANY, MD, MPH, LAURA TRUPIN, MPH,
LINDSEY A. CRISWELL, MD, MPH, EDWARD YELIN, PhD, and PATRICIA P.
KATZ, PhD
The publisher's final edited version of this article is available at Arthritis Care Res
(Hoboken)
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Abstract
Objective
To determine the validity of standardized screening assessments of cognitive functioning

to detect neuropsychological impairment evaluated using a comprehensive battery in
systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
Methods
This is a cross-sectional study using a combined cohort of 139 persons with SLE and 82
persons with RA. Screening cut points were empirically derived using receiver operating
characteristic curves and threshold selection methods. Screening measures included the
Hopkins Verbal Learning Test-Revised (HVLT-R) learning and delayed recall indices and
phonemic fluency, a composite measure of the 3 cognitive screening tests, and the
Perceived Deficits Questionnaire-Short Form (PDQ-SF), a self-report measure of
cognitive symptoms. A comprehensive neuropsychological battery was administered as
the gold standard index of neuropsychological impairment.
Results
Rates of neuropsychological impairment were 27% and 15% for the SLE and RA cohorts,
respectively. Optimal threshold estimations were derived for 5 screening techniques. The
HVLT-R learning and phonemic fluency indices yielded the greatest sensitivity at 81%.
The PDQ-SF yielded the lowest sensitivity at 52%. All measures were significantly
associated with neuropsychological impairment after controlling for relevant
sociodemographic covariates and depression.
Conclusion
These results suggest that telephone-administered screening techniques may be useful
measures to identify persons with neuropsychological impairment. Specifically, measures
of phonemic fluency and verbal learning appeared to be most sensitive and least likely to
misclassify impaired individuals as cognitively intact. Self-reported questionnaires may
have relatively decreased sensitivity compared to standardized interviewer-administered
cognitive measures.
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Introduction
Neuropsychological impairment is among the most common neuropsychiatric
manifestations of systemic lupus erythematosus (SLE), with prevalence rates reaching as
high as 81% of patients (1). Although individuals with rheumatoid arthritis (RA) are
considered to be less likely to develop neuropsychological impairment, recent studies
have highlighted the burden of such impairment in RA, with prevalence rates ranging
from 30% to 50% (2,3). For most, cognitive dysfunction represents a decline in
comparison to their previous level of functioning and may increase the risk of impairment
in activities of daily living. In the clinic, patients commonly report cognitive dysfunction
that is perhaps milder in severity, yet very troublesome to the patient and detrimental to
their daily function. While a routine neuropsychological evaluation would be beneficial
for most individuals with suspected neuropsychological impairment, there are many
reasons why this option is often not readily available, including lack of access to
neuropsychological services, costs of comprehensive evaluations, and time constraints.
To promote rapid identification of patients who may benefit from a comprehensive
neuropsychological evaluation or to identify patients in large-scale research studies,
pragmatic screening approaches to identify patients with cognitive impairment are
necessary.
A number of very brief bedside and telephone screening approaches have been developed
and validated for use primarily with older adults, and the majority of these instruments
are modifications of mental status examinations. Although these approaches are brief,
they lack sensitivity in detecting the kinds of impairments characteristic of rheumatic
conditions (4). Additionally, subjective symptoms of cognitive decline or measures based
on perceptions of cognitive functioning are often not confirmed by neuropsychological
testing and are influenced by psychiatric states, including depression (5).
The purpose of this study was to determine the utility of telephone cognitive screening
approaches and self-report assessments of cognitive symptoms in detecting
neuropsychological impairment for individuals with SLE and RA. While a
comprehensive neuropsychological evaluation remains the gold standard for research
and practice, brief screening approaches hold value in that they may rapidly identify
those at greatest need for services or facilitate large-scale research to study cognitive
compromise in rheumatic diseases and other chronic medical conditions.
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Subjects and Methods

Subjects and data collection method
Two hundred twenty-one individuals (139 with SLE and 82 with RA) residing in the San
Francisco Bay area were recruited for a comprehensive clinical study including in-person
assessments of cognition, psychiatric status, body composition, and physical function at
the University of California, San Francisco (UCSF) Clinical and Translational Science
Institutes Clinical Research Center (CRC). Exclusion criteria for this study included non
English speaking, age <18 years, daily dose of 50 mg or greater of oral prednisone,
pregnancy, uncorrected vision problems interfering with reading ability, and joint
replacement within the past year. SLE participants were drawn from the UCSF Lupus
Outcomes Study, a prospective study of 957 individuals with diagnostically confirmed
SLE. Details about enrollment and data collection for this study have been reported
previously (6). Briefly, subjects were recruited through academic medical centers (25%),
community rheumatology offices (11%), nonclinical sources, including support groups
and conferences (26%), and the media (38%). Diagnostically confirmed RA participants
were drawn from the UCSF RA panel, which has also been described previously (7).
Briefly, the RA panel began in 1982 with 822 patients, supplemented with 4 additional
enrollment periods between 1989 and 2003. Individuals with RA were recruited from a
random sample of board-certified rheumatologists practicing in northern California. The
primary data collection method for both cohorts is through annual telephone interviews,
including screening measures of cognitive impairment. Telephone interviews and CRC
visits were separated by a mean SD interval of 1.7 2.5 months.
Evaluators at the CRC were trained by a licensed clinical psychologist (LJJ) over the
course of 6 weeks to conduct evaluations using standardized procedures, including
assessments observed by the trainer. This research protocol was approved by the UCSF
Committee on Human Research. All of the participants gave their informed consent to
participate.
Sociodemographic factors, disease characteristics, and depression

measures
Sociodemographic and disease characteristics were collected through the telephone
interview to describe the sample and included age, sex, race/ethnicity, education,
household income, and disease duration (years). The presence versus absence of a
diagnosis of major depressive disorder was determined at the in-person assessment
through the use of the Mini International Neuropsychiatric Interview (8), a structured
interview to determine diagnoses for the major axis I psychiatric disorders in the
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and the
International Statistical Classification of Diseases and Related Health Problems, Tenth
Edition that has been deemed reliable and valid (8).
Measures of neuropsychological impairment

To determine the presence of neuropsychological impairment during the in-person
assessment, a battery of tests was modified from the American College of
Rheumatologyrecommended 1-hour battery for SLE and represented our gold
standard approach to determine the presence of cognitive impairment (9). This battery
has been previously determined to be reliable and valid in SLE (10). To accommodate
possible RA-related hand motor impairment, the battery was modified to minimize hand
motor demands or control for hand motor speed. The battery and indices used for
analyses included: 1) verbal learning and recall: the California Verbal Learning Test-II
(CVLT-II) (11) learning trials 1 through 5, short delay free recall, long delay free recall,
and recognition indices; 2) nonverbal learning and recall: the Rey Complex Figure Test
copy trial (12), immediate delay, and long delay; 3) fluency: the Controlled Oral Word
Association Test (COWAT) (13) total correct on phonemic fluency (letters) and semantic
fluency (animals) and the Delis-Kaplan Executive Function Test (DKEFS) design fluency
test; 4) executive functioning: the DKEFS ColorWord Inhibition Test (inhibition
condition), DKEFS Card-Sorting Test (total correct, set 1), and the DKEFS Trail-Making
Test (shifting condition controlling for sequencing speed); 5) working memory and
speeded processing: Symbol Digit Modalities Test oral version (total correct) (14) and
Digit Span Backwards (15); and 6) visuospatial functioning: the Judgment of Line
Orientation test short form (total correct) (16).
A total of 16 indices of neuropsychological functioning were generated, and impairment
was assigned if performance fell below 1 SD of the population normative data. Using a
conventional approach, patients were classified as having neuropsychological impairment
if they were impaired on at least 5 of the 16 indices (10).
Screening measures of neuropsychological impairment

Screening measures were selected based on the presence of an analogous measure in the
gold standard battery, feasibility of use over the telephone (e.g., no visual stimuli),
sensitivity for deficits characteristic of rheumatic conditions, and brevity. The screening
measures required approximately 1215 minutes of administration time and included: 1)
verbal learning and recall: the Hopkins Verbal Learning Test-Revised (HVLT-R) (17)
learning condition and delayed recall condition, and 2) fluency: the COWAT phonemic
fluency. Alternative letters were used for the telephone COWAT to minimize practice
effects. An analogous impairment index was created in addition to the individual indices
that consisted of impairment on any of the 3 cognitive measures at less than or equal to
1 SD below the population norms. Respondents were asked to participate in the telephone
interview in a room free from distractions and interruptions and were instructed not to
prepare or write anything down during the testing. Test examiners were survey
interviewers who received training and supervision by a licensed clinical psychologist
(LJJ), including practice administrations, observed administrations, and reliability checks.
Cognitive symptoms were assessed with the Perceived Deficits Questionnaire-Short
Form (PDQ-SF) (18), previously used in SLE (19). The PDQ-SF consists of 5 questions
covering 4 categories: attention/concentration, retrospective memory, prospective
memory, and planning/organization. Respondents rate difficulties using a 4-point Likert
scale (0 = never to 4 = almost always). Total scores range from 0 to 20, with higher
scores reflecting increasing symptoms.
Statistical analyses
Descriptive statistics were used to characterize participant sociodemographics, disease
duration, and rates of neuropsychological impairment. Zero-order correlation coefficients
were calculated to evaluate associations among screening measures and the
comprehensive test battery. To determine optimal screening cut points, receiver operating
characteristic (ROC) curves were estimated and the Youden threshold selection method
was utilized. Briefly, the Youden Index has been used as a measure of diagnostic test
accuracy in clinical epidemiology and determines the maximum vertical distance from
the ROC curve to the diagonal reference or chance line, i.e., the optimal cut point
corresponds to the point on the ROC curve farthest from the reference line (20). Finally,
multivariate linear regressions were conducted using screening measures to determine the
degree to which each screening test can predict the number of neuropsychological indices
impaired after controlling for relevant sociodemographics and depression.
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Results
Patient and neuropsychological performance characteristics of the 139 SLE and 82 RA
patients are shown in Table 1. Impairment rates on any single index ranged from 8%
(digit span) to 32% (Rey Complex Figure Test copy). SLE patients demonstrated
impairment on a mean SD of 3.5 3.1 indices compared to a mean SD of 2.4 2.2
indices for the RA cohort. Overall neuropsychological impairment was present in 25%
and 10% of SLE and RA patients, respectively. Rates of impairment on the screening
battery ranged from 20% and 14% (HVLT-R learning index) to 46% and 38%
(impairment on at least 1 of 3 indices) for the SLE and RA cohorts, respectively. Mean
SD scores for the PDQ-SF were 8.6 4.3 and 5.6 3.7 for SLE patients and RA patients,
respectively. Inter-correlations among screening tests and the neuropsychological battery
are shown in Table 2, with significant correlations among screening tests and their
analogous tests in the comprehensive battery (i.e., HVLT-R learning and CVLT-II
learning: r = 0.52, P < 0.0001; HVLT-R delay and CVLT-II long delay: r = 0.48, P <
0.0001; COWAT letter fluency: r = 0.78, P < 0.0001), as well as among screening tests
and neuropsychological impairment indices (screening impairment index and
neuropsychological impairment index: r = 0.29, P < 0.0001). The PDQ-SF was
significantly but less robustly associated with neuropsychological impairment (r = 0.15,
P < 0.05).
Table 1
Patient and neuropsychological performance characteristics of SLE and RA patients*
Table 2
Correlations among cognitive screening measures and the neuropsychological battery in
SLE and RA*
ROC curves were generated using the entire group (not shown) and empirically derived
thresholds were estimated along with the 95% confidence interval estimates of precision
(Table 3). The COWAT thresholds yielded the highest sensitivity (79%) and the highest
negative predictive value (0.93). The PDQ-SF cut point yielded the lowest sensitivity and
negative predictive values of 0.55 and 0.87, respectively. Classification for SLE and RA
cohorts are also shown in Table 3.
Table 3
Empirically derived cut points for cognitive screening measures as compared to
impairment on the full neuropsychological battery*
Separate multivariate linear regressions were conducted using each screening measure as
a predictor of the number of neuropsychological indices impaired controlling for
education, ethnicity, sex, income, and the presence of major depressive disorder, followed
by a final regression including the entire screening battery (Table 4). The PDQ-SF was
the only screening measure that did not significantly predict neuropsychological
impairment after controlling for demographics and depression. Phonemic fluency 34,
HVLT-R learning 26, and HVLT-R delay 9 were all significant predictors of
neuropsychological impairment, accounting for 11%, 13%, and 14% of the variance after
accounting for demographics and depression, respectively. The 4 measures as a cognitive
battery collectively predicted 26% of the variance independent of depression and
demographics.
Table 4
Separate multivariate linear regression analyses predicting the number of
neuropsychological indices impaired*
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Discussion
The purpose of this study was to determine the criterion validity of telephoneadministered cognitive screening tools in identifying individuals with neuropsychological
impairment. Results suggest that telephone screening measures of learning, recall, and
fluency were relatively sensitive (sensitivity rates reaching 79%), modestly specific
(specificity rates ranged from 60% to 70%), and unlikely to classify an impaired
individual as being intact (negative predictive value ranged from 90% to 93%). After
controlling for sociodemographics and depression, the neuropsychological screening
measures were significant predictors of neuropsychological impairment, but the selfreport measure was not an independent predictor of impairment.
The self-reported measure of cognitive symptoms was a less sensitive screening measure
for neuropsychological impairment, suggesting slightly decreased validity in detecting
neuropsychological impairment. Despite these limitations, self-report measures may have
a role in clinical practice and research. These measures provide an evaluation of an
individual's perception of their cognitive abilities, and may indicate very mild cognitive
changes noticeable to the patient but not yet detectable on the examination. Additionally,
comparisons of these measures to informant-based measures and objective
neuropsychological testing can provide important information about a patient's insight
into their own functioning (21). An additional limitation is related to the precision of
estimates based on a smaller sample size of cognitively impaired participants in the
disease-specific analyses. In particular, sensitivity point estimates were susceptible to
decreased precision as evidenced by the wider confidence intervals, most notably in the
RA sample. Further, the relatively low positive predictive values in comparison to the
high negative predictive values suggest that these measures may have some advantage in
identifying with greater confidence patients who do not have neuropsychological
impairment as compared to the relatively reduced confidence in identifying patients who
would have neuropsychological impairment. Further, the use of published normative data
to classify impairment may be somewhat disadvantageous, and a local matched control
group may have alleviated some problems with national normative data. Our cohort may
have differed somewhat from national data, particularly with respect to higher education
levels, which could have biased our results primarily by underestimating impairment in
this study.
The burden of neuropsychological impairment in rheumatic disease is increasingly
recognized, and given limited resources, we continue to seek brief but sensitive
approaches to detect cognitive impairment for both research endeavors and clinical
practice. We present data suggesting that existing standardized screening measures can be
feasibly administered by telephone and have adequate utility in identifying patients with
neuropsychological impairment. For both clinical and research purposes, these measures
hold promise as a means to identify patients who would meet criteria for cognitive
impairment, or clinically would be candidates for more comprehensive
neuropsychological testing. Estimates of specificity and sensitivity for the single
measures were very comparable to existing single-measure screening approaches
available in other conditions (22). Screening measures are best interpreted in
collaboration with a provider that is competent in neuropsychological assessment to
ensure appropriate clinical interpretation. Through the use of such screening techniques,
we may facilitate the identification of cognitive impairment in patients and potentially
reduce the risk of a range of poor health and functional outcomes.
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Significance & Innovations
The burden of cognitive impairment is high in systemic lupus erythematosus

and increasingly recognized in rheumatoid arthritis.
Screening measures to rapidly identify individuals with suspected cognitive
impairment for large-scale research and clinical purposes are necessary.
Three standardized screening measures of learning, recall, and fluency
demonstrated adequate sensitivity in detecting cognitive impairment.
Self-reported measures of cognitive symptoms were less sensitive measures to
identify individuals with cognitive impairment.
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Acknowledgments
The contents are solely the responsibility of the authors and do not necessarily represent
the official views of the NIH.
Supported by the NIH/National Center for Research Resources, University of California,
San Francisco Clinical and Translational Science Institute (grant UL1-RR024131), the
NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant
P60AR053308), the NIH/National Institute of Mental Health (grant K08MH072724), and
the Rosalind Russell Medical Research Center for Arthritis.
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Footnotes
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it critically for important
intellectual content, and all authors approved the final version to be published. Dr. Julian
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 conception and design. Julian, Yelin, Katz.
Acquisition of data. Julian, Trupin, Criswell, Yelin, Katz.
Analysis and interpretation of data. Julian, Yazdany, Trupin, Yelin.
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12. Meyers JE, Meyers KR. Rey Complex Figure Test. Psychological Assessment
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Memory Test-Revised: professional manual supplement. Psychological Assessment
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Jurnal 7
Int J Gen Med. 2011; 4: 325332.
Published online 2011 April 20. doi: 10.2147/IJGM.S16492
PMCID: PMC3108200
Multimodal neurophysiological and

psychometric evaluation among patients
with systemic lupus erythematosus
Ghaydaa A Shehata,1 Yasser MB Elserogy,2 Hossam Eddin K Ahmad,2 Mohamed I
Abdel-Kareem,3 Ashraf M Al-kabeer,4 Mohamed M Rayan,2 and Mohamed ES Abd ElBaky2
This article has been corrected. See Int J Gen Med. 2011 July 28; 4: 547.
This article has been cited by other articles in PMC.
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Abstract
Objective:
To determine some of the neuropsychiatric manifestations of systemic lupus
erythematosus (SLE) by applying multimodal neurophysiological and psychometric
studies.
Patients and methods:

Twenty-six SLE patients were evaluated for neurological and psychiatric disorders and
compared with 26 healthy controls matched for age, sex, education, and social class. The
severity of SLE disease was assessed. Each subject was subjected to the following
examinations: laboratory, neurophysiology, magnetic resonance imaging of the brain,
transcranial duplex, Modified Mini-mental State Examination, Cognitive Assessment
Scale Inventory, Hamilton Depression Scale, and Hamilton Anxiety Scale.
Results:
The mean age of subjects was 25.9 8.9 years. The most prevalent neurological
manifestations were (in order of frequency) anxiety in 17 cases (65.4%), depression in 15
cases (57.7%), headache in 10 cases (38.5%), peripheral neuropathy in 7 cases (26.9%),
seizures in 6 cases (23.1%), psychosis in 5 cases (19.2%), dementia in 4 cases (15.4%),
radiculopathy in 4 cases (15.4%), myositis in 3 cases (11.5%), and stroke in 2 cases
(7.7%). There was a significant affection in amplitude of the ulnar nerve, cognitive
function impairment, and electroencephalography changes. There was a significant
increased mean velocity and decreased Pulsatility Index of the most studied intracranial
vessels in the patients.
Conclusion:
The use of multimodal neurophysiological, transcranial duplex, and psychometric scales
increases the sensitivity for detecting nervous system involvement.
Keywords: SLE, SLEDAI, cognitive function, depression, anxiety, neurological
disorders
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Introduction
Systemic lupus erythematosus (SLE) is a multisystem disease with a spectrum of clinical
manifestations and a variable course characterized by exacerbation and remission.1 In the
course of SLE, a variety of neuropsychiatric disturbances is reported, with prevalence
rates ranging from 17% to 75%.2 The challenge in patients with SLE is to determine
whether neuropsychiatric affection is functional due to a psychogenic basis or an organic
abnormality such as dysfunction of the central or peripheral nervous system.1
Furthermore, if the cause is organic, are those symptoms or findings due to lupus itself
(either active or inactive) or to other causes? A previous report3 on the prevalence of
neuropsychiatric affection from most to least prevalent is as follows: cognitive
dysfunction, headache, mood disorder, cerebrovascular changes within intracranial
vessels, seizures, polyneuropathy, anxiety, and psychosis.
The use of multimodal neuropsychiatric evaluations is essential for diagnosis of early

affection. Electroencephalography (EEG) may be helpful to confirm changes or diffuse
encephalopathy.1 Electromyography (EMG) and nerve conduction studies (NCS) provide
useful data in the clinical assessment of peripheral complications of SLE.4 Transcranial
duplex (TCD) confirms that subclinical cerebrovascular changes affect intracranial
vessels in SLE.4 The aim of the present study was to characterize the potential
neurological involvement of unselected SLE patients and index of disease activity.
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Patients and methods

Twenty-six SLE patients (24 females and 2 males) with ages ranging from 10 years to 40
years were selected at the outpatient clinic wards of Assiut and Al-Azhar (Assiut)
University Hospitals, Egypt. All patients met the diagnostic criteria of SLE.5
Rheumatologic evaluation was completed using the Systemic Lupus Erythematosus
Disease Activity Index (SLEDAI).6 Exclusion criteria included: i) age below 10 years or
more than 40 years; ii) pre-existing clinical cardiovascular or cerebrovascular events
(angina, myocardial infarction, transient ischemic attack, or stroke); iii) other systemic
diseases (such as renal, liver, or endocrinal diseases) or taking drugs known to have
central nervous system effects; or iv) cancer discovered in the previous 5 years.
Medications at the time of the study included nonsteroidal anti-inflammatory drugs,
prednisone (1020 mg/d) in all cases and disease-modifying anti-rheumatic drugs
(hydroxychloroquine, azathioprine, methotrexate, and cyclophosphamide).
SLEDAI measures the current status of SLE disease activity according to clinical and
laboratory manifestations. SLE disease activity is defined as the reversible manifestations
of the underlying inflammatory process.6 SLEDAI consists of 24 weighted attributes,
which are grouped into 9 domains, called organ systems (weighting in parenthesis):
central nervous system (8), vascular (8), renal (4), musculoskeletal (4), serosal (2),
dermal (2), immunologic (2), constitutional (1), and hematologic (1). SLEDAI is a
reliable and valid instrument for measuring the clinical state of SLE patients.6,7
Twenty-six healthy individuals matched for age, sex, number of education years, and
socioeconomic status8 were selected as a control group from relatives of patients. These
control groups were examined and fully investigated.
The Regional Ethical Committee of Assiut University Hospitals and Al-Azhar (Assiut)
approved the study. All subjects gave their written informed consent for participation.
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Methods
All subjects (patients and control) were subjected to full medical, neurological, and
rheumatological examination and socioeconomic status assessment.8 Multimodal
neurophysiological and psychometric tests were applied for all subjects. Venous blood
was obtained from all subjects by puncturing an antecubital vein at 8 a.m. after overnight
fasting. A complete blood count was performed using automated cell counter, and blood
urea and serum creatinine were measured by the spectrophometeric method. Normal
ranges were as follows: blood urea 3050 mg/dL and serum creatinine <1.5 mg/dL.9
Liver function tests were performed by a spectrophotometeric method using Stat Fax
(Awareness Technology, Dubai, United Arab Emirates). Normal ranges were as follows:
aspartate aminotransferase 035 U/L and alanine aminotranferease 035 U/L.10 Fasting
blood glucose was measured by spectrophotometeric method, complete urinalysis was
performed by microscopic examination, and 24-hour collection of urine protein was by
spectrophotometeric method. Disease activity indexes such as erythrocyte sedimentation
rate using the western green tubes method were considered normal when less than 10
mm/hour.11 Antinuclear (ANA) and anti-double-stranded DNA (anti-dsDNA) were
measured using enzyme-linked immunosorbent assay method and determined in controls
to exclude the presence of autoimmune diseases.
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Imaging studies
All subjects underwent magnetic resonance imaging of the brain and transcranial duplex
(TCD). TCD was carried out using Nicolet Bravo model 460 SNF0000001544
(Neurocare, Madison, WI) with a 2 mHz probe, which provided a direct and noninvasive
assessment of subclinical atherosclerosis. TCD examinations were performed at the
Department of Neurology and Psychiatry, Clinical Neurophysiology Unit, Assiut
University Hospital. The right anterior cerebral artery (ACA) was assessed via
transtemporal window. The depth of insonation was between 60 mm and 90 mm with
subject head in a neutral position. The right middle cerebral artery (MCA) was assessed
via a transtemporal window. The depth of insonation was between 30 mm and 60 mm
with subject head in a neutral position. Right posterior cerebral artery (PCA) was
assessed via transtemporal window. The depth of insonation was between 60 mm and 80
mm with subject head in a neutral position. Right vertebral artery (VA) was assessed via
suboccipital window. The depth of insonation was between 60 mm and 90 mm with
subject head in a neutral position. Right basilar artery (BA) was assessed via suboccipital
window. The depth of insonation was between 80 mm and 120 mm with subject head in a
neutral position. Systolic mean velocity (MV) and Pulsatility Index (PI) were recorded as
PI equal to the peak velocity minus the end-diastolic velocity divided by the MV.12 The
PI normal range is 0.51.1.13
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Neurophysiologic studies
Conventional 20-minute EEG recordings were obtained using the 8-channel Nicolet
Bravo model 460 SNF0000001544. The electrodes were placed on the scalp according to
the International 1020 System of Electrode Placement using bipolar and referential
montages. Hyperventilation was used as a provocative test. Seizures were divided into
epilepsy (chronically recurrent seizures occurring in a stereotypic pattern corresponding
to anatomically focal spikes on EEG) and isolated seizures (usually corresponding to
generalized slowing on EEG).
Motor nerve conduction velocity (MCV) studies were performed on the right ulnar,
median, and common peroneal nerves. MCV, distal latency (DL), and amplitude of
compound muscle action potential (CMAP) were measured with standard surface
stimulating and recording techniques. The latency was measured from the stimulus onset
to the beginning of the initial deflection of the CMAP. The MCV can be calculated by
stimulating at two different points along the nerve and measuring the latency for each
response. F-wave (for median, ulnar, and common peroneal nerves) was measured by
putting the recording electrodes on the distal muscle innervated by the testing nerve,
employing the belly-tendon method. F-wave latency was measured from the start of the
stimulus to the onset of initial deflection of the F-wave with the shortest latency. The
latency of the F-wave after distal stimulation is usually in the range of 2333
milliseconds for median and ulnar nerves in normal individuals and of 5060
milliseconds for the peroneal nerves.
An H-reflex study was measured by placing the recording electrodes on the
gastrocnemius muscle and stimulating the posterior tibial nerve at the popliteal fossa. The
latency was measured from the start of stimulation to the onset of the initial deflection of
the H-reflex. The latency of the H-reflex is usually in the range of 2535 milliseconds in
normal individuals.
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Psychometric
The Cognitive Abilities Screening Instruments (CASI) consists of 25 test items and
provides quantitative assessment of attention, concentration, orientation, memories for
post-knowledge and present input, language abilities, drawing and writing abilities, listgenerating ability, abstract thinking, and judgment.14 The CASI is more comprehensive
than most screening tests of cognitive abilities and can be used to screen for early
cognitive impairment and dementia. We considered the cutoff of CASI as that according
to Ross et al,15 which is 67 points for dementia. The Mini-mental State Examination
(MMSE) is a widely used scale for screening for dementia.16 Most of the subjects of the
present study were illiterate. The two points testing reading and writing were excluded,
and the full score was calculated as 28 instead of 30 points. The cutoff point of dementia
was 21 instead of 23 points.17 In the present study, dementia was diagnosed if the
clinical presentation fulfilled criteria of dementia as well as when the subject scored 21
on the MMSE and 67 on the CASI.18 The Hamilton Depression Scale is a widely used
and reliable scale and not specific for elderly people.19 The cutoff point of depression in
this scale is 17, according to Michele and Bolino.20 Numerous authors have since
investigated the dimensionality of the scale and demonstrated that it is
multidimensional.19 The Hamilton Anxiety Scale lists 14 types of symptom. The total
score ranges from 0 to 56. A total score of 18 or more means anxiety.21
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The computer software package SPSS for Windows (Version 16) (IBM, Chicago, IL,
USA) was used for the data analysis. Continuous variables such as age were expressed as
mean standard deviation, whereas categorical variables such as gender were presented
as frequencies (%). The Pearson Chi-square test and independent-sample t-test did not
assume equal variances were used. A series of Pearson correlation coefficients was used
to examine SLEDAI and different variables. Significance level was set at P 0.05.
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Results
Details of demographic data, systemic examination, and laboratory data are illustrated in
Tables 1 and and2.2. There were nonsignificant differences between cases and controls
with regard to age, sex, number of education years, and socioeconomic status. The most
prevalent neuropsychiatric manifestation was anxiety in 17 cases (65.4%), depression in
15 cases (57.7%), headache in 10 cases (38.5%), peripheral neuropathy in 7 cases
(26.9%), isolated seizures in 6 cases (23.1%), psychosis in 5 cases (19.2%), dementia in 4
cases (15.4%), radiculopathy in 4 cases (15.4%), myositis in 3 cases (11.5%), and stroke
in 2 cases (7.7%).
Table 1
Demographic data of patients and control group
Table 2
Clinical, laboratory, radiological, and neurological data of the patients
Electrophysiological and EEG data are summarized in Tables 3 and and4.4. There was a
significant difference between amplitude of motor NCS of the ulnar nerve of SLE
patients and the control group, which means an increased incidence of ulnar axonal
neuropathy in SLE patients. Abnormal EEG findings such as high-voltage slow waves
and spike slow waves and sharp waves were observed in 19 cases (73.1%) of SLE but in
only 6 cases (23.1%) in the control group.
Table 3
Motor conduction studies of peripheral nerves in cases compared with the control groups
Table 4
Electroencephalograph (EEG) in cases compared with the control group
Table 5 illustrates the significant decline in most studied cognitive function tests among
the SLE group compared with the control group. In addition, there were higher results in
the Hamilton Depression Scale and Hamilton Anxiety Scale. There was a significant
increased MV and decreased PI of most studied intracranial vessels in both patient groups
compared with the control group. There was a significant increased MV of ACA and VA
and nonsignificant decreased PI of most studied intracranial vessels in the patient group
compared with the control group (Table 6).
Table 5
Cognitive function, depression, and anxiety in patients compared with control
Table 6
Intracranial vessels affection in patients and control
To examine the relationship between SLEDAI cognitive function subscales, laboratory
findings, and TCD studies of all patient groups (Table 7), a series of Pearson correlation
coefficients was calculated. There were significant negative correlations between
SLEDAI and short-term memory, CASI drawing and fluency, and MCA and PCA PI.
Table 7
Pearson correlation between systemic lupus erythematosus disease activity index and
cognitive function subscales, laboratory findings, TCD studies
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Discussion
Neurophysiological and psychometric studies may help to characterize the potential
meaning of subclinical neurological involvement. Moreover, they may favor more
accurate diagnosis and may provide clinicopathological information regarding its
nature.23 In this study, neurophysiological studies helped in the diagnosis of neurological
abnormalities in clinically silent neurological or psychiatric disorders in patients with
SLE. The most common type of neuropsychiatric abnormalities recorded in this study
was anxiety, followed by depression, headache, peripheral neuropathy, seizures,
psychosis, dementia, radiculopathy, myositis, and stroke.
Among NCS, the amplitude of MCV of the ulnar nerve is significantly reduced among
SLE patients compared with the control group. These changes indicated predominant
axonal neuropathy rather than demyelinating neuropathy among SLE patients. That can
be explained by vascular changes rather than other pathological causes of neuropathy,
although the pattern of MCV does not permit such a differentiation without a nerve
biopsy. This was in agreement with results obtained by Khedr et al in 2001.24 They noted
a significant reduction in amplitude of motor NCS of ulnar, median, and common
peroneal nerves among SLE patients compared with the control group. Also, our results
were in agreement with Hanly,25 who reported that sensorimotor neuropathy had been
found in up to 28% of SLE patients and frequently occur independently of other disease
characteristics.8
Abnormal EEG findings were observed in 19 cases (73.1%) but in only 6 cases (23.1%)
in the control group. That result was in agreement with Khedr et al in 200124 in which
abnormal EEG findings were observed in 73% of cases. In the present study, the most
common abnormality was diffuse slow activity, which is generally considered a sign of
organic brain disease and is the most common EEG abnormality recorded for SLE.24
This is matched with previous studies that reported EEG abnormalities among SLE
patients.24,27 In addition, there are significant differences between lupus patients and
controls with regard to most studied EEG findings.
Among the many neurological involvements of SLE, cognitive impairment is becoming
increasingly recognized.24 Cognitive function is significant impairment in patients with
SLE in comparison with controls in the present study, mainly in short- and long-term
memories, attention, mental manipulation/concentration, fluency, and total scores of
MMSE and CASI scales. There is no specific or unique pattern of cognitive impairment
in SLE, and many individual patients have subclinical deficits. For example, a review of
14 cross-sectional studies of cognitive function in SLE revealed subclinical cognitive
impairment in 11%54% of patients.25 Fisk et al28 reported that two patterns of memory
dysfunction had been identified in SLE patients. Impaired remote memory appears to be
associated with a history of past central nervous system (CNS) involvement (suggesting
the presence of a residual neurological deficit), whereas impaired immediate memory and
concentration implies increased disease activity that may represent transient and diffuse
CNS effects.28 These deficits are not specific to one brain region or one
neuropsychological process, and may reflect both multifocal and diffuse brain diseases.
Monastero et al29 proposed that a frontal temporoparietal dysfunction might account for
the cognitive deficits found in patients with SLE. Positron emission tomography
(PET)/single photon emission computed tomography (SPECT) studies30 revealed a
hypoperfusion in the frontal, temporal, and parietal lobes mainly in SLE patients.
However, we cannot be completely sure that these cognitive changes are due to the lupus
itself or possibly to a manifestation of chronic disease not specific to SLE or
neurospsychiatric SLE. A recent paper by Hanly et al31 demonstrated that there was
essentially no difference between SLE, rheumatoid arthritis, and multiple sclerosis
patients in cognitive function.
There were significantly higher scores for Hamilton Depression Scale and Hamilton
Anxiety Scale in patients with SLE than in the control group, which matches the study by
Nery et al.32 Thirty-five cases out of 71 (49.2%) presented with major depression, and 37
cases (52.1%) presented with anxiety disorders. Several factors might explain these high
prevalence rates and include the stress of having a chronic disease and the high doses of
corticosteroids commonly used in its treatment.33 On the other hand, there is intriguing
evidence suggesting that some patients with SLE may have organic forms of depression
caused by autoimmune lesions in the CNS. For instance, the antiribosomal P antibody is
highly associated with both lupus psychosis and severe depression.33 Furthermore,
neuropsychiatric disorders due to SLE activity, such as seizures, strokes, aseptic
meningitis, delirium, and psychosis, may also be associated with concomitant depressive
symptoms.33 Nery et al32 hypothesized that the high prevalence of some anxiety
disorders could be linked to feelings of embarrassment experienced in public by some
SLE patients due to the skin and facial disfigurements that can result from the disease or
treatment. Although a magnetic resonance imaging scan of the brain in all cases was
normal, there was early detection of cerebrovascular affection using TCD findings in this
study. The middle cerebral artery stem is relatively easy to study. Ultrasound has a
sensitivity and specificity of 90%99% for finding a stenosis or an occlusion. For the
more difficult to image intracranial segment of the vertebral arteries and the BA,
ultrasound has a sensitivity of 70%80% and a specificity of 90%99%.34
There are significant increased mean velocities and decreased PI of most studied
intracranial vessels. In previous studies, most pathologic conditions affecting the large
intracranial arteries result in narrowing, constriction, stenosis, or occlusion of the vessel,
which results in increased mean flow velocity and decreased PI.13,35 These results were
matched with a study35 of 167 patients with SLE evaluated by the TCD technique.
Results could not be obtained for 14 patients due to technical difficulties. In the
remaining 153 patients, results of 138 TCD techniques were normal, and 15 patients (9%)
had one or more abnormalities.36
Our results are consistent with the recent article by Gasparovic et al,37 which
demonstrated increased cerebral blood flow and cerebral blood volume that could be
consistent with increased mean velocities and decreased PI. This basically demonstrated
that neurospsychiatric SLE is often associated with hyperperfusion and that the areas of
decreased perfusion observed by PET or SPECT may actually be normal perfusion in
certain situations and misinterpreted as areas of reduced perfusion. Our results are
consistent with this interpretation. Increased mean velocities and decreased PI could be
due to cerebrovasodilation and increased cerebral blood flow.37
In this study, abnormalities on TCD (PI) were significantly correlated with clinical
disease activity as measured by SLEDAI in the form of MCA (P = 0.035 and PCA (P =
0.021). These results agree with those of the study by Kron et al.36 These abnormal
findings in TCD in this study can be attributed to the development of vascular changes in
SLE, which lead to narrowing and stenosis of cerebral blood vessels.
SLEDAI is a reliable and valid instrument for measuring the clinical state in patients with
SLE.37 In this study, significant negative Pearson correlations were found between
SLEDAI, MCA PI, PCA PI, and some cognitive function tests such as short-term
memory, drawing, and fluency. In addition, significant positive correlation was found
between SLEDAI and ANA laboratory findings. The study of SLEDAI and its
correlations is important. With most human attributes, SLE disease activity cannot be
measured directly. What is being measured is the observed phenomenon that indicates the
existence of this attribute. Assessment of SLE disease activity is challenging due to the
multisystem nature of this disease with its diverse range of possible manifestations, as
any part of the body can be affected. Furthermore, involvement of a system could lead to
various manifestations, adding to its complexity.38,39 Moreover, we can explain these
significant correlations as an increase in severity of the disease with more deterioration in
cognitive function.
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Footnotes
Disclosure
The authors report no conflicts of interest or funding in this work.
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References
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17. Farrage AF, Farweez HM, Kheder EH, et al. Prevalence of AD and other dementing
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18. Khedr EM, Hamed SA, El-Shereef HK, et al. Cognitive impairment after
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21. Moller HJ. Methodological aspects in the assessment of severity of depression by the
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Jurnal 8
J Multidiscip Healthc. 2011; 4: 6372.
Published online 2011 April 5. doi: 10.2147/JMDH.S19303
PMCID: PMC3093952
Psychosocial dimensions of SLE:

implications for the health care team
Nancy L Beckerman,1 Charles Auerbach,1 and Irene Blanco2
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Abstract
Background:
The purpose of this exploratory study was threefold, ie, to clarify the unique psychosocial
challenges facing those living with systemic lupus erythematosus (SLE), to distinguish
which sociodemographic variables impact the lives of SLE patients, and generate
knowledge regarding the way patients perceive SLE medication regimens.
Methods:
This was a cross-sectional exploratory study in 378 patients diagnosed with SLE and
receiving services from the SLE Lupus Foundation in New York City. In addition to
sociodemographic variables, the instrument used consisted of two scales, ie, the Systemic
Lupus Erythematosus Needs Questionnaire (SLENQ) and the Multidimensional Health
Locus of Control Scale, as well as questions regarding subjective perceptions of side
effects from SLE medication.
Results:
The highest general cause of self-reported depressive and anxious feelings was changes
in appearance due to SLE, and limitations in physical abilities due to SLE (primarily
from muscle and joint pain). The higher the sense of control over SLE, the less likely
respondents were to report feeling depressed and anxious. African-American and
Hispanic SLE patients reported a higher level of unmet psychological needs due to SLE
than did their other ethnic counterparts. Weight gain and hair loss were the most likely
medication side effects and also the most likely causes of SLE-related depression and
anxiety.
Conclusion:
Those living with SLE are at risk for feelings of depression and anxiety. AfricanAmerican and Hispanic women are at higher risk for these emotional states.
Comprehensive assessment across the disciplines should screen this group of patients for
depression and anxiety, and be prepared to refer them to patient education and social
work counseling as indicated.
Keywords: lupus, psychosocial impact of illness, multidisciplinary
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Introduction
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with acute periodic
flare-ups of symptoms impacting any organ system and resulting in potentially lifethreatening complications.1,2 Some of the significant complications of treatment include
hirsutism, weight gain, osteoporosis, osteonecrosis, accelerated atherosclerosis, and
retinal damage.3,4 These side effects and complications can lead to significant functional
and emotional challenges. Patients often experience a high degree of psychological

symptoms, including anxiety, depression, mood disorders, and decreased health-related
quality of life.58 This article reports on the findings from a preliminary exploratory
study on how patients living with SLE perceive their SLE-related challenges. This was a
hypothesis-generating study to tease out some of the nuances of the psychosocial
challenges for this population.
While there are various empirical studies across the health care disciplines on the
psychosocial impact of SLE illness, these studies identified general psychosocial
experiences without identifying some of the more complex emotional needs of those
living with SLE in the US.811 This study included several instruments, including one
that had only been used once previously, ie, the Systemic Lupus Erythematosus Needs
Questionnaire (SLENQ) and another known as the Multidimensional Health Locus of
Control, that had not ever been used with the SLE population previously. There are many
biopsychosocial implications of SLE that have been shown to precipitate depression and
anxiety. The disease itself, unexpected exacerbations, medical regimen side effects, and
medical care issues are often identified as the sources of depressed feelings.1418 One
complex nuance, that has not been addressed fully, is how much does disease activity
influence emotional states such as depression and anxiety? And which disease
manifestations create the most emotional distress? A patient being treated for disease
activity will have medical and nursing needs, and will likely have needs for occupational
and physical therapy, as well as social work counseling.811 The disease
disproportionally impacts women (9:1), and women will experience physical changes,
such as rashes or a cushingoid appearance, which can trigger feelings of low self-esteem,
depression, and anxiety at significantly higher rates than those of healthy women.1220
Danoff-Burg and Friedberg studied the unmet needs of 112 SLE patients. Key findings
regarding the impact of SLE included tiredness (94%), need for assistance about feeling
anxious or depressed (78% and 71%, respectively), and nearly half (48%) desired
assistance related to maintaining relationships with friends.5 These findings are
consistent with similar international research on the psychosocial impact of SLE.11
Moses et al developed and used an SLENQ specifically for 386 SLE patients from a
support association in Australia to ascertain their unmet psychosocial needs.12 Five of
the highest levels of unmet needs were in the psychological domain. They found that
need for help with psychosocial and lifestyle problems outranked the needs for
information.12 A key implication from this study was that SLE patients should be
assessed early on for the likelihood of depressive sequelae.
The current range of multidisciplinary literature indicates that SLE patients have a high
vulnerability for self-reported feelings of depression and anxiety.1519 It is unclear
which SLE manifestations contribute to the forms of psychosocial distress occurring most
often, which sociodemographic cohorts may be at higher risk for such psychosocial
distresses, and the nature of the physical and emotional sequelae of SLE medication
regimens. We therefore performed a cross-sectional study of 378 SLE patients to identify
these psychosocial experiences and which ethnicities may be at risk for which
psychosocial stressors.
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Materials and methods

Participants and procedures
All 899 individuals in the New York SLE Lupus Foundation contact database were sent
the survey instrument. All patients had self-reported having SLE. To protect anonymity,
chart reviews were not part of the exploratory process. Each respondent received a sixpage survey to investigate their psychosocial experiences of living with SLE. The survey
instrument was written at an eighth-grade reading level and was also available in Spanish.
The survey was completely anonymous and deidentified. An informed consent letter was
sent along with each survey that explained the purpose of the study, its voluntary nature,
that participants could discontinue without any penalty, and that the information would be
used in the aggregate with no identifying information. To maintain the anonymity of
patients responses, survey completion was used instead of a signature on the informed
consent letter. Packets were distributed to home mailing addresses with stamped
envelopes, so that completed surveys could be bulk-mailed to the researchers at Yeshiva
University with complete anonymity. Of the 899 questionnaires originally distributed, 19
were returned unopened due to a change of address. Of 880 received, a total of 378
individuals responded to the survey in English or Spanish (336 in English and 42 in
Spanish), with an overall return rate of 42.9%.
Instrument
The survey instrument comprised four components. Part one included sociodemographic
variables including gender, race, and age, as well as time of diagnosis, length of
diagnosis, education, employment, and relationship status.
Part two consisted of two scales, ie, the SLENQ, developed and validated by Moses et
al,12 which uses a 5-point Likert scale (1 = no need, 3 = moderate need, 5 = high need)
for 12 different psychosocial factors. For example, the SLENQ asks: How much
assistance do you need with your change in appearance due to SLE? and How much
assistance do you need because you have anxiety about SLE.12 For the purpose of
analysis, three subscales were created from the psychosocial need items, ie, depression,
anxiety, and socioeconomic coping. Depression was assessed by the following items:
feeling depressed due to limitations caused by SLE; feeling depressed because of changes
in the body; and feeling depressed because of side effects. Anxiety regarding SLE was
assessed by the following items: feeling confused about why this disease happened to
you; anxiety about changes in your appearance; feeling angry about having SLE; feeling
uncertain about the future; dealing with anxiety about SLE; and anxiety about side
effects. Socioeconomic coping consisted of the following items: concerns about gaining
employment; satisfactory performance in job; and coping with extra costs. The SLENQ
subscales have been validated, with higher scores reflecting higher need.11 Reliability of
the subscales was high, with coefficent alphas of 0.91 for depression, 0.90 for anxiety,
and 0.76 for economic coping. One-way analysis of variance was utilized to test how
various factors like age, educational level, employment, and race impact psychosocial
need.
In part three, the second scale was used, ie, the Multidimensional Health Locus of
Control Scale measuring the respondents subjective perceptions of how much control
they had over their SLE.21 Two subscales, ie, chance and internal, were utilized in
this research. Chance refers to the mindset that the course of ones illness is out of ones
control. Internal refers to the opposite perspective, ie, If I manage my illness with diet,
exercise, compliance with medication regimens, I can control its course. Each is a sixitem self-report questionnaire that uses a 6-point Likert scale, with items ranging from 1
(disagree very much) to 6 (agree very much). Examples of items included in the chance
subscale are: No matter what I do, I am going to get sick, and Most things that affect
my health happen to me by accident. Examples of items included in the internal subscale
are: If I get sick, it is my own behavior which determines how soon I get well again
and I am in control of my health. It is important to note that the subscales are
independent of each other. The internal reliability for these subscales was good, with a
coefficent alpha of 0.76 for chance and 0.77 for internal. Each subscale can range
between 1 (lowest need) and 6 (highest need).
Part four concluded with open-ended questions about the range of medication regimens,
side effects, and psychosocial impact of those medication regimens.
The data were analyzed using SPSS (v 17.0; SPSS, Inc, Chicago, IL) and STATA (v 11.0;
Stata Corp, College Station, TX). Statistical tests used in this analysis included the Chisquare, t-test, and analysis of variance. Ordinary least squares regression was used to
analyze the Likert scale questions on the SLENQ and Multidimensional Health Locus of
Control scales. Ordinary least squares regression was used to perform a multivariate
analysis in order to evaluate how the different variables affected the outcome measures of
depression, anxiety, and socioeconomic coping derived from the SLENQ. The indicators
internal and chance were entered as continuous variables. African-American,
Hispanic, and Asian were contrasted with White; education was coded as some college,
college, and advanced degree, and contrasted with high school or less education. How the
respondents rated their experience with SLE was also coded as chronic symptoms and
frequent flares, and contrasted with infrequent flares. Finally, insurance was coded as
Medicaid, Medicare, and no insurance, and contrasted with private insurance. Coef in
Table 2 indicates the slope which shows how much the degree of an outcome variable
(depression, anxiety, or socioeconomic coping) changes for every point increase in a
covariate (chance, internal). For example, when chance increases by 1, a respondents
level of depression increases by 0.17 points. A respondent who had a score of 5 on this
scale would have a 0.85-point increase (5 0.17) in their degree of depression.
Postestimation Wald tests were utilized to test the significance of indicator variables, such
as race and insurance. With regards to missing data, some respondents did not respond to
every question, so some items were tabulated with less than the total number of
respondents. List-wise removal of missing data was utilized because missing cases were
not missing at random.
Table 2
Ordinary least squares regression for three outcome variables
Each of the subscales on the SLENQ, ie, depression, anxiety, and socioeconomic coping,
ranges from 1 (no need) to 5 (high need). It has been reported that formal statistical
tests for normality are especially undesirable as they will have low power in the small
samples where the distribution matters and high power only in large samples where the
distribution is unimportant.22 Given the relatively large sample size of nearly 400
subjects reported here, the means and the medians were compared for overall skew. When
the mean and median are equal, it indicates that the distribution is symmetrical. The
criterion of symmetry is met for each scale. Parametric tests perform well with large
samples (more than 100) even when the data are non-normal.23 As a result, the t-test and
one-way analysis of variance were utilized to compare groups of respondents. The
criterion for statistical significance in this study was an alpha level of 0.05.
Regarding ordinary least squares regression analysis, each of the regression models was
tested for normality of residuals, homoscedasticity, multicollinearity, model specification,
and linearity. The residuals in all three models deviated slightly from normality. Lumley
et al point out that linear regression does not require any assumption of normal
distribution in sufficiently large samples. Previous simulations studies show that
sufficiently large is often fewer than 100 .22 The BreuschPagan test for
heteroskedasticity was conducted for the models. The results were nonsignificant,
indicating homogeneity of their respective residuals. The variance inflation factor was
calculated to test for the presence of collinearity in each model. All models had mean
variance inflation factors close to 1, and no independent variable had a variance inflation
factor above 2, indicating that the independence assumption was met. The models were
tested for model specification errors, which can inflate regression coefficents. This type
of error occurs when a relevant variable is omitted or an irrelevant one is included. The
Ramsey RESET Test was utilized to test for this type of error. The results indicated that
the coefficents in each of the models were not influenced by a model specification error.
Finally, by utilizing scattergrams between the outcome variables and key independent
variables, the models met the linearity assumption.
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Results
Sample characteristics
As expected, the vast majority of respondents (n = 357, 96.5%) were women. Age ranged
from 20 to over 67 years, with approximately one-third under 35 years (n = 97, 26%),
one-third aged 3645 years (n = 100, 27%), and one-third aged 46 years (n = 123, 33%).
The majority of respondents were non-White women, with 40% (n = 144) identifying
themselves as African-American and 38% (n = 135) as Hispanic. A large majority of the
group was either unemployed (19.4%) or receiving disability due to SLE (44%). Most of
the respondents (70.4%) had been diagnosed with SLE more than 5 years earlier and, in
the last 12 months, more than one-third (37.3%, n = 139) had been hospitalized because
of complications from SLE. The most frequent type of medical coverage for the
respondents was Medicaid (44.7%, n = 168), followed by private coverage (29.1%). The
primary source of medical care for the majority of respondents was provided by a private
physician (53.95%, n = 191) followed by clinics (37.9%, n = 134). Further demographic
and socioeconomic data are listed in Table 1. The sociodemographic variables of this
sample were representative of the national profile of this population regarding age, race,
and ethnicity.19 The only significant divergence was for education. This sample had a
higher level of education than what is reported in most lupus studies.611
Table 1
Demographics of a sample with systemic lupus erythematosus (n = 378)
Two hundred and twenty-eight (60.58%) respondents indicated that their SLE was
marked by a chronic set of symptoms. Another 16.23% (n = 61) had frequent flares, while
19.13% (n = 72) reported infrequent flares. Joint aches, fatigue, and muscle pain were
present for at least two-thirds of the respondents. Respondents reporting chronic
symptoms or frequent flares had higher psychosocial needs as determined by their mean
scores, ie, depression (3.8 1.1, P = 0.000), anxiety (3.7 1.1, P = 0.000), and
socioeconomic coping (3.3 1.2, P = 0.043), as compared with those having infrequent
flares. The level of detail was fairly broad. Specific disease manifestations, such as retinal
damage and renal damage, did not emerge.
SLE needs questionnaire
Participants responded concerning their level of psychosocial needs using the SLENQ, as
previously detailed. Figure 1 displays the median scores for each factor from lowest to
highest need for psychosocial support or assistance. Needing some form of psychosocial
assistance for coping with their feelings of depression because of changes in body and
changes in appearance was rated as their highest concern.
Figure 1
Psychosocial problems.
Each of the subscales, ie, depression, anxiety, and socioeconomic coping, ranged from 1
(no need) to 5 (high need). The scales had the following overall means and medians:
depression mean = 3.5 1.3, median = 3.7, interquartile range = 2; anxiety mean = 3.3
1.2, median = 3.3, interquartile range = 2; and socioeconomic coping mean = 2.9 1.3,
median = 2.7, interquartile range = 2.3. The means and medians indicate that respondents
had the most difficulty coping with depression, followed by anxiety and socioeconomic
coping. Lumley et al point out that respondents reporting chronic symptoms or frequent
flares are more likely to have higher psychosocial needs with their depression, anxiety,
and socioeconomic coping, as compared with those having infrequent flares.22 Those
who reported frequent flares had a mean score of 3.8 1.1 for depression (P = 0.000), a
mean of 3.7 1.1 for anxiety (P = 0.000), and a mean of 3.3 1.2 (P = 0.043).
Respondents reporting chronic symptoms also reported significantly higher psychosocial
needs on depression and anxiety compared with those reporting infrequent symptoms.
The means were 3.6 1.2 and 3.4 1.2, respectively.
Education impacts the level of perceived psychosocial need, mediating levels of selfreported depression and anxiety associated with SLE. For depression, respondents with a
high school education or lower rated their psychosocial need as 4.0 1.1 compared with
those who obtained college or advanced degrees (3.2 1.3 and 3.0 1.5, respectively, P
< 0.001). A similar pattern existed for anxiety, where respondents with high school
education or less had an average need of 3.8 1.2 compared with 3.0 1.2 for
respondents who had obtained at least a college degree (P = 0.001).
Respondents who were unemployed or receiving disability insurance had higher
psychosocial needs on all three subscales. Those who were more fully employed reported
less distress with depression, anxiety, and socioeconomic coping. For depression,
respondents on disability rated their need as 3.8 1.2 compared with 3.1 1.4 and 3.1
1.3 for those working part time or full time (P < 0.001). A similar pattern was true for
anxiety, where respondents receiving disability had a mean of 3.6 1.2 compared with
3.0 1.2 and 3.1 1.2 for respondents working full time and part time, respectively (P =
0.001).
Hispanic respondents demonstrated the highest need for psychosocial assistance on all
three subscales. For feelings of depression, Hispanic respondents rated their need for
assistance as 3.8 1.2 compared with 3.5 3.5 for African-Americans, 2.9 1.3 for
Asians, and 3.2 1.4 for White respondents (P = 0.009). On anxiety, Hispanic
respondents rated their need for psychosocial assistance as 3.5 1.2 compared with 2.8
1.1 for Asians, 3.3 1.2 for African-Americans and 3.0 1.2 for Whites (P = 0.013). For
socioeconomic coping, White respondents displayed little need for assistance, with a
mean of 2.3 2.3 compared with 3.1 1.3 for Hispanics, 2.9 1.3 for AfricanAmericans, and 3.0 1.0 for Asians. Respondents on Medicaid rated their psychosocial
needs highest on the depression and anxiety subscales. Those who indicated a lack of
insurance rated the highest need for assistance with socioeconomic coping. The mean on
the depression subscale for Medicaid recipients was 3.9 1.2 compared with 3.2 1.2
for those who utilized private insurance (P < 0.001). Medicaid recipients rated the
anxiety subscale highest, with a mean of 3.6 1.1 compared with a mean of 3.1 1.3 for
Medicare beneficiaries (P = 0.006). Respondents without insurance had the highest need
for assistance with socioeconomic coping, with a mean of 3.6 1.2 as compared with a
mean of 2.5 1.3 for Medicare recipients, 3.2 1.3 for Medicaid recipients, and 2.6 1.2
for those receiving private insurance (P = 0.0001). The scales had the overall means of
3.5 1.3 for depression, 3.3 1.2 for anxiety, and 2.9 1.3 for socioeconomic coping.
These means indicate that respondents had the most difficulty coping with depression,
followed by anxiety and socioeconomic coping.
The analyses of SLE manifestations revealed that those with muscle pain and hair loss
were the most likely to report feelings of SLE-related depression and anxiety.
Respondents reporting muscle pain had a mean score of 3.8 1.2 for depression
compared with 2.9 1.3 for those who did not (P < 0.001). The respondents experiencing
muscle pain also had higher levels of anxiety with a mean of 3.7 1.1 compared with 2.8
1.1 for those who were not experiencing pain (P < 0.001). Those who experienced hair
loss had a higher level of depression, with a mean of 3.9 1.2 compared with 3.1 1.3
for those who did not experience this side effect (P = 0.000). Respondents reporting
chronic symptoms or frequent flares were more likely to have higher psychosocial needs
with their depression, anxiety, and socioeconomic coping, as compared with those having
infrequent flares. Those who reported frequent flares tested higher for depression, with a
mean of 3.8 1.1 (P = 0.0000) and higher for anxiety, with a mean of 3.7 1.1 (P =
0.000).
Those who experienced hair loss also had higher levels of anxiety, with a mean of 3.6
1.2 compared with 3.0 1.2 for those who did not experience this side effect (P = 0.000).
Similarly, those with muscle pain had higher levels of socioeconomic need, with a mean
of 3.0 1.3 compared with 2.6 1.3 for those who did not (P = 0.006).
Multidimensional health locus of control scale findings

The more respondents perceived they had some control over the illness, the less likely
they were to report high levels of depression or anxiety. The mean and median scores for
the chance and internal subscales on the Multidimensional Health Locus of Control Scale
were: mean 2.84 1.2, median 2.7, interquartile range 1.5, and mean 2.98 1.2, median
3.0, interquartile range = 1.6, respectively, across all patients. Respondents who reported
their SLE as having mostly infrequent flares (mean 2.5 1.2) perceived that they had
more control over their health compared with those with chronic symptoms (mean 2.9
1.2) or infrequent flares (2.8 0.98, P = 0.002).
In Table 2, the column labeled Coef is the slope. This indicates how much the degree of
an outcome variable (depression, anxiety, and socioeconomic coping) changes for every
point increase in a covariate (eg, chance, internal). The critical locus of control finding
was that the more control a patient felt they had over their disease, the less likely they
were to report feelings of depression and anxiety, with the specific variances detailed in
Table 2.
Depression
The most significant locus of control finding was that for those who reported the
sensation of having no control over their disease; chance (Coef = 0.169, P = 0.007)
were positively associated with more chronic symptoms (Coef = 0.648, P = 0.001),
frequent flares (Coef = 0.796, P = 0.001) and depression (Coef = 0.648, P = 0.001). A
college degree (Coef = 0.561, P = 0.010) or advanced degree (Coef = 0.644, P =
0.026) compared with a high school degree or less was associated with requiring less
assistance with depression, as was the case with having Medicare as compared with
having private insurance, Medicaid patients required more assistance than those with
insurance. The results of the postestimation test indicated that, compared with Medicaid
recipients, respondents receiving Medicare had a decreased need for psychosocial
assistance with depression (0.589, P = 0.008).
Anxiety
The following covariates significantly increased the need for psychosocial assistance for
feelings of anxiety: chance (Coef = 0.138, P = 0.019) and frequent flares (Coef = 0.686,
P = 0.003) as compared with infrequent flares, and the following covariates decreased the
degree of need for psychosocial assistance for feelings of anxiety: college degree (Coef =
0.538, P = 0.011) compared with high school. The results of the postestimation test
indicated that compared with respondents with no health insurance, respondents receiving
Medicare had a decrease in need for psychosocial assistance for feelings of anxiety (Coef
= 0.483, P = 0.039).
Socioeconomic coping
Being African-American (Coef = 0.488, P = 0.041), having muscle pain (Coef = 0.380, P
= 0.038) and having no insurance (Coef = 1.09, P = 0.001) all significantly increased the
need for psychosocial assistance for socioeconomic needs. The results of postestimation
indicated that, compared with respondents with no health insurance, respondents
receiving Medicare had a statistically significant decrease in the need for assistance with
economic coping (P = 0.034).
Medication result
In analyzing the medication regimens and side effects, it is important to note that
respondents could and often did report use of various combinations of drugs. Because the
side effects can be a result from any one medication, a combination of SLE medications,
or indeed a disease manifestation, the significance of their responses is biased. Because
most patients were taking more than one medication at a time, it is difficult to ascertain
which specific medications gave rise to which side effects Nevertheless, their perceptions
of medication side effects is significant because they may have misinterpreted side effects
incorrectly, and may have titrated their own medication regimens based on erroneous
perceptions and beliefs. It is also important to glean which side effects are experienced as
being the most distressing to these patients, so that treating physicians can assess these
issues as they develop or adjust treatment plans. At least one-third of the respondents
used hydroxychloroquine, azathioprine, vitamins, methotrexate, steroids, or antiinflammatory medications. There are many expected and some unexpected side effects of
SLE medications that present a myriad of physical and emotional challenges. Most
respondents experienced either hair loss (51.1%) or weight gain (32.7%) as side effects
from the use of their respective medications. Table 3 displays the relationship between
medications for SLE and the types of side effects respondents experienced from them.
Those utilizing hydroxychloroquine and steroids experienced the most side effects. Over
two-thirds of those who experienced hair loss (66.4%) or weight gain (67.4%) were
taking hydroxychloroquine (P = 0.02).
Table 3
Type of drug by side effects
Another set of interesting findings involved respondents perceptions of the advantages of
SLE medications, as well as their respective emotional preferences for medication
treatment plans. The chief reported benefit of these medications was the reduction in
frequency and intensity of flares. When respondents were queried about what they would
desire from a new medication for SLE, a majority (55%, n = 207) desired fewer flares
and almost one-third (32%, n = 120) desired fewer side effects. Although most
respondents experienced side effects of hair loss or weight gain from their medications,
they still expressed that their primary desire from a new medication was fewer flares.
Almost two-thirds (62.4%) of those who experienced hair loss desired fewer flares (P =
0.01) in a new medication, and 44% who experienced weight gain also desired fewer
flares (P = 0.01).
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Discussion
Because this was an exploratory study with a broad focus, it has several inherent
limitations and biases. Chief among these is the lack of confirmatory American College
of Rheumatology diagnoses. Nevertheless, these were patients who reported themselves
as being SLE patients, and were being treated for SLE by rheumatologists. The second
critical limitation is that the majority of this sample was on various combinations of SLE
medications, and therefore it is difficult to discern which side effects were the results of
which treatments. This study highlighted several complex psychosocial reactions that are
associated with SLE. Some specific correlations between these factors were uncovered in
this cohort. This study reveals an association between chronic symptoms and the
likelihood of higher reports of depression and anxiety, but not specifically the cause and
dynamic effect. This may be a bidirectional association, in which chronic disease activity
influences emotional states or, in fact, that feelings of depression and anxiety triggers
more disease activity.
The sequelae of SLE that may predict higher vulnerability for a depressive reaction
include more reports of depression attributed to changes in appearance (particularly hair
loss and weight gain) and limitations due to SLE (particularly due to muscle pain and
joint pain) as was found by Moses12 in Australia, Shorthall et al24 in England, and
Dobkin et al.25 This finding was also consistent with that of Ng,26 who found that selfesteem for women living with SLE was negatively impacted by changes in body
appearance, such as weight gain and hair loss.
When responding to the SLENQ, the sample overwhelmingly reported that the highest
general cause of depressive and anxious feelings was changes in appearance and
limitations in physical abilities due to SLE, primarily muscle and joint pain. The more
chronic the symptoms, the more likely that feelings of depression would arise. The more
frequent the flares, the more intense the emotional distress. These correlations between
symptomatology and emotional distress are consistent with the findings of other
psychosocial researchers in this area, and our sample represents a larger and more
ethnically diverse sample.27
Learning that African-Americans and Hispanics report a higher vulnerability for SLErelated depression and anxiety, as well as poorer socioeconomic coping than their White
and Asian counterparts, is an important finding. This should alert the health care team to
integrate social supports into treatment for this population and inform those who develop
program service delivery for this population. This finding is consistent with those of other
studies reporting health disparities among race and class, ie, the larger burden of disease
that Hispanics and African-Americans carry, as well as higher mortality and complication
rates.28,29 From our data, it is unclear what role language or cultural barriers play in the
higher rates of depression reported by Hispanics. This can be further clarified in future
research. While all SLE patients should be assessed comprehensively, Hispanic and
African-American women may require more psychosocial resources and support, and
every effort has to be made to provide culturally competent assessment and
intervention.30,31 It is critical to appreciate the psychological impact of this illness and
the negative side effects of various medical regimens and how these may impact mood
changes, and as Moses and Ng found, feelings of low-self-esteem, capacity for self-care,
and medication compliance.12,2426 The Hispanic cohort reported the most emotional
distress and reported facing the most socioeconomic distress.
The data also found that the more one perceives control over the illness and the more
education one has, the less likely one is to report feeling depressed or anxious about SLE
challenges. This is an important finding because there have been no other psychosocial
studies which were able to confirm this important relationship. A related study
demonstrated that SLE patients with lower levels of education tend to be more anxious,
as well as less compliant with visiting their physician.27,28 Some possible suppositions
about this correlation are that the more educated one is, the better one may be able to
understand SLE, and the more resources one may have to cope more adaptively.3,4
Identifying that those affected by muscle pain and hair loss tend to be more vulnerable to
feelings of depression and anxiety is significant for treating physicians, as well as for
individual and group counselors. One has to consider the dynamic interplay of the disease
manifestations and the emotional state, because muscle pain and hair loss could influence
depression and anxiety. The converse is also possible, ie, that depression and anxiety
could result in both muscle pain and hair loss. Individual and group counseling with SLE
patients should allow for exploration and expression of feelings about these specific SLE
manifestations and the range of potentially troubling side effects from SLE
medications.29 Clinical initiatives and program development should emphasize patient
education and advocacy because this has been found to be a mitigating factor in both
depression and anxiety for this population.31
The great majority of SLE patients on medication experience a wide range of side effects,
the most prominent of which is hair loss and weight gain, and yet when asked what they
wanted from a new medication, the answer was fewer flares. It is difficult to be
definitive regarding certain side effects because some patients may interpret an SLE
symptom as a side effect, eg, they may report that Plaquenil is causing hair loss, but it is
also possible that increased SLE activity is the culprit. For many, if they are on steroids,
they have active disease, which has its own sequelae.
The prevalence of emotional distress for this population would indicate that intake,
assessment, and treatment include inquiry into the psychosocial impact of the illness,
with a focus on depression, anxiety, and socioeconomic coping. Assessment should pay
particular attention to how a patient has been coping with any changes in appearances and
limitations due to SLE, as well as the emotional impact of any side effects they may be
experiencing. Any adjustments that can be made to medical regimens with negative side
effects should be considered wherever possible. The issue of control for an SLE patient
may include information, patient education, and advocacy, as well as emphasizing selfactualization for patients in the use of their resources and psychosocial support.12 SLE
patients manifesting signs of depressive thinking, anxiety, and difficulty in
socioeconomic coping, should be referred to social workers who should employ active
therapeutic approaches, such as crisis intervention and task-centered counseling, to

combat the unpredictable nature of SLE.32
Identifying and confirming that feelings of depression and anxiety occur at significant
rates for those living with SLE is critical. Those working in health care should be alerted
to which SLE populations are at higher risk, ie, Hispanic and African-American women,
and which manifestations trigger the greatest likelihood of feeling depressed and anxious,
ie, changes in appearance due to SLE, limitations in physical abilities, joint pain, and
weight gain.
Depression and anxiety are broad terms that can reflect very different levels of intensity
and frequency for each patient. The SLENQ should be accompanied by the Iverson
Depression scale in future research in order to gain more precision for health care
treatment.33 The overriding study question for future research is how does the
depressed state influence disease activity, disease management, and psychosocial
experience of the disease? In addition, further studies should examine SLE patients
longitudinally to determine how patients cope adaptively and what strengths (internal and
external) aid in the resilience of patients coping with this chronic disease over time.
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Conclusion
This study explored self-reported states of depression and anxiety in SLE patients using
the SLENQ instrument, as well as the relationship between perceived sense of control
and states of depression and anxiety for the SLE patient. Key findings demonstrated that
individuals with SLE were more likely to experience depression and anxiety when there
were changes in body appearance due to SLE, and to experience limitations in physical
abilities due to SLE, primarily due to muscle and joint pain. The higher the perceived
sense of control over SLE, the less likely respondents were to report feeling depressed
and anxious. African-American and Hispanic SLE patients reported a higher level of
unmet psychological needs than did their other ethnic counterparts. Weight gain and hair
loss were the most likely medication side effects, and the most likely to trigger SLErelated depression and anxiety.
Whether the health care provider is the treating physician, nurse, social worker, or any
other member of a health care team, it is essential to assess this population for how
emotional states may impact disease activity, self-care, and medication compliance. The
SLENQ proved a reliable, valid, and comprehensive assessment tool for identifying
psychosocial needs related to SLE. The health care team treating this population should
be alert to the potential psychosocial impact of SLE, such as depression and anxiety.
Health care providers should include comprehensive biopsychosocial screening and
assessment wherever possible, and make referrals where needed in order to address the
emotional sequelae of living with SLE.
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Footnotes
Disclosure
This research received no specific grant from any funding agency in the public,
commercial, or not-for profit sectors. The authors report no conflicts of interest in this
work.
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Jurnal 9
Arthritis Care Res (Hoboken). Author manuscript; available in PMC 2012 August 1.
Arthritis Care Res (Hoboken). 2011 August; 63(8): 11781187.
doi: 10.1002/acr.20489
PMCID: PMC3149725
Neurocognitive Impairment in
Childhood-onset Systemic Lupus
Erythematosus: Measurement Issues in
Diagnosis
Tricia S. Williams, PhD, Cynthia Aranow, MD, Gail S. Ross, PhD, Alexandra Barsdorf,
PhD, Lisa F. Imundo, MD, Andrew H. Eichenfield, MD, Philip J. Kahn, MD, Betty
Diamond, MD, and Deborah M. Levy, MD MS
The publisher's final edited version of this article is available at Arthritis Care Res
(Hoboken)
Go to:
Abstract
Objectives
To assess the prevalence of neurocognitive impairment (NCI) in childhood-onset
systemic lupus erythematosus (cSLE) comparing published classification criteria, and to
examine associations between NCI, disease characteristics, psychosocial-well being and
intelligence.
Methods
cSLE patients and ethnicity- and age-matched healthy controls completed a
neuropsychological research battery, and results were categorized by three different NCI
classification criteria with different cutoff scores (e.g., >2, 1.5, or 1 SD below mean) and
number of required abnormal tests or domains.
Results
Forty-one cSLE subjects and 22 controls were included. Subjects were predominantly
female (70%) and Hispanic (70%). Executive functioning, psychomotor and fine-motor
speed were most commonly affected. Method 1 classified 34.1% of cSLE subjects with
NCI, compared to Method 2 (14.6% with decline and 7.3 % with NCI) and Method 3
(63.4% with NCI). Prevalence of NCI was not significantly different between controls
and patients using any of the categorization methods. NCI was not associated with SLE
disease activity or characteristics, or with depression. Using Method 3, patients in the
cognitive impairment group reported significantly lower quality of life estimates (69.7 vs
79.3, p=0.03). Below average intellectual functioning (IQ < 90) differentiated the number
of test scores >1 and >1.5 SD, but not >2 SD below the mean.
Conclusions
NCI was prevalent in cSLE, but varied according to chosen categorization method. A
similar proportion of cSLE patients and controls had NCI, reinforcing the importance of
studying an appropriate control group. Categorical classification (i.e.
impaired/nonimpaired) may oversimplify the commonly observed deficits in cSLE.
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Introduction
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with diverse
manifestations involving multiple organ systems. Neurocognitive impairment is one of
the 19 distinct neuropsychiatric syndromes of SLE (NPSLE) defined by the American
College of Rheumatology,1 and is associated with considerable morbidity among both
adults and children with SLE.14 Since 15 to 20 percent of all patients with SLE have the
onset of disease in childhood, cognitive impairment may have a substantial impact on
learning, academic and vocational success. However, a major roadblock to accurate
prevalence estimates and to our understanding of neuropsychological functioning among
patients with childhood-onset SLE (cSLE) can be attributed to the lack of a standard
criteria for neurocognitive impairment (NCI).2
The American College of Rheumatology (ACR) defines cognitive impairment as a deficit
in at least one of the following seven broad cognitive domains: 1) simple or complex
attention, 2) memory, 3) visual-spatial processing, 4) language, 5) reasoning and problem
solving, 6) psychomotor speed and 7) executive functioning.1 Cognitive impairments may
be mild to severe, represent a decline from previous functioning, and are associated with
an impact on social, educational and/or occupational functioning. The ACR definition
also stipulates that neuropsychological testing is mandatory for NCI diagnosis.
Neuropsychological batteries, by definition, employ several tests to assess each of the

neurocognitive domains. In research, test and/or domain aggregate scores are then used to
stratify individuals into a dichotomous category of neurocognitive impairment
(present/absent) using varying criteria as to how far scores (test and/or domain) depart
from test standardization sample expectations (e.g., 1, 1.5 or 2 standard deviations below
normative sample averages). Given this variation in NCI criteria cutoffs, it is not
surprising that prior studies report a prevalence of NCI in cSLE that ranges between 20
and 95 percent.514 This broad range may also be attributed to the different number of
tests and/or domains required for diagnosis of impairment. Furthermore, interpretation
of prevalence estimates is complicated by varying study designs and sample
characteristics (i.e., patients referred for clinical assessment versus prospective research
study, and the inclusion of control samples).
Three recent studies with the goal of determining NCI in SLE used clearly defined, but
varying classification criteria methodologies.57 In the first method, Brunner et. al.
employed a NCI cutoff of more than 2 standard deviations below the standardized mean
in 1 domain, or scores between 1 and 2 standard deviations below the mean in 2 or more
domains.5 In their study, 4 domains (memory, psychomotor speed, visual construction
processing and attention-executive functioning) were assessed using 11 tests; and 59% of
the sample (research recruitment) met NCI criteria. A second method outlined (but not
tested) by expert consensus methodology assigns impairment status to individuals who
score more than 2 standard deviations below the normative mean in 1 or more domains
and an intermediate category of cognitive decline to individuals achieving scores
between 1.5 and 1.9 standard deviations below published norms in 1 or more domains.6
This publication also discussed focal impairment (impairment in one domain) and
multifocal impairment (impairment in more than 1 domain). Most recently, a third
method outlined by Muscal et. al. operationalized NCI as 2 or more single test scores
more than 1.5 standard deviations below normative means spanning two cognitive
domains.7 Seven domains (as recommended by ACR: memory, psychomotor speed,
visual construction processing and attention, executive functioning, intelligence, and
academics) were assessed using 19 individual tests, and the prevalence of NCI ranged
between 47 and 71% depending on cohort (prospective versus. retrospective).
These studies offer formal NCI criteria for cSLE; however their different definitions and
sample characteristics as well as lack of healthy control comparisons preclude consistent
estimates of the prevalence of NCI in cSLE. This reduces the sensitivity to successfully
identify NCI in cSLE and subsequently hinders appropriate intervention for children with
persistent cognitive challenges. Therefore, the primary objectives of our study were to a)
to assess how use of these different NCI criteria changes the prevalence rates in a sample
of predominantly urban, non-white cSLE patients, and b) to determine whether cSLE
patients are significantly more likely to be categorized as having NCI than a matched
control group using these differential NCI criteria methods.57 Our secondary objectives
were to determine the associations between NCI, disease characteristics, psychosocialwell being and intellectual level in this cohort.
Go to:
Patients and Methods

Participants
Individuals with cSLE followed at the Lupus Clinic at the Morgan Stanley Childrens
Hospital of New York-Presbyterian, Columbia University Medical Center were eligible
for recruitment as part of a prospective longitudinal study of neurocognitive function
between June 2006 and August 2009. The data presented here represents the baseline
neuropsychological assessment. Inclusion criteria for all participants were: 1) age 10 21
years, 2) English-speaking or fluently bilingual, attending school in English for at least
two years, and ability to complete traditional neuropsychological testing in English, and
3) absence of a co-morbid condition affecting cognitive functioning (e.g., cerebral palsy,
Downs syndrome). Consecutive eligible patients attending Lupus Clinic were
approached until the recruitment goal of 50 subjects was attained. Five eligible patients
declined participation. A control sample of age, socioeconomic (SES) and ethnicitymatched individuals was recruited. Control subjects were predominantly friends of the
cSLE subjects; however, a small number of healthy siblings of the cSLE subject with no
history of SLE or other autoimmune disease and healthy neighborhood controls were also
recruited. The study was approved by the Institutional Research Board at Columbia
University Medical Center.
Procedures
Demographic data collected included age, gender, zip code and family income. Screening
psychosocial measures included the Beck Depression Inventory (BDI)15 and the standard
Pediatric Quality of Life Inventory (PedsQL).16 For the cSLE subjects, disease
information collected included date of diagnosis, current medications, disease activity
and damage and any documented history of NPSLE as defined by the ACR case
definitions.1 No subjects had previously completed a neuropsychological assessment.
Disease activity was evaluated using the Systemic Lupus Erythematosus Disease Activity
Index, (SLEDAI, score range 0 105)17 and disease-specific damage scores using the
Systemic Lupus International Collaborative Clinics damage index score (SDI, score
range 047)18 at the rheumatology visit preceding their neuropsychological evaluation.
Recent laboratory results (dsDNA, complements, complete blood count, urinalysis) were
collected in order to complete the disease activity measures. The presence of
antiphopholipid antibodies (anticardiolipin antibodies and/or lupus anticoagulant) since
cSLE diagnosis was documented.
Neuropsychological functioning was evaluated using a research battery of traditional
neuropsychological tests adapted and expanded from the recommended ACR battery for
assessment of adults with SLE1 in order to be suitable for evaluation of a cSLE
population. The battery assessed seven overall cognitive domains: (1) memory, (2)
language and verbal reasoning, (3) visual-spatial reasoning, (4) executive functioning, (5)
psychomotor speed, (6) fine motor dexterity and (7) academics). This is representative of
the seven domains recommended by the ACR, but differentiates fine motor control from
higher level psychomotor processes and adds assessment of academic functioning,
relevant to the pediatric population. Neuropsychological testing was performed by a

trained psychometrist and supervised by a pediatric neuropsychologist using multiple
measures as detailed below and in Table 2. Assessments typically took 3 to 4 hours to
complete. Twenty-three tests were administered to evaluate the seven domains. Individual
tests were included from the following nine test batteries: (1) Weschler Abbreviated Scale
of Intelligence (WASI) for problem solving and reasoning skills, comprised of four
subtests;19 (2) Wide Range Assessment of Memory and Learning (WRAML-2) for
immediate learning and memory, comprised of four subtests;20 (3) Letter Fluency from
the Delis Kaplan Executive Functioning System (DKEFS);21 (4) Comprehensive Trail
Making Test Parts 1 and 5;22 (5) Stroop Color and Word Test Childrens Version (four
subtests);23,24 (6) Wechsler Intellectual Scales, Adult and Child Versions (WAIS III /WISC
IV) Subtests of Letter-Number Sequencing and Digit Coding;25,26 (7) Purdue Pegboard
(three subtests);27 and (8) Wide Range Achievement Test - Third Edition (WRAT-III).28 In
analyses examining how other neurocognitive domains varied by intellectual functioning,
full scale intellectual scores were used to compare the remaining five domains: (1)
executive functioning, (2) memory, (3) psychomotor speed, (4) fine motor dexterity and
(5) academics. Z-scores (representing standard deviations from the tests standardization
sample mean) were generated for each test. Overall mean z-scores were then determined
for each subject in each of the seven cognitive domains. The number of individual tests
and domain scores falling below three different cutoff impairment levels were also
computed (e.g., >1, >1.5 and >2 standard deviations (SD) below the test mean).
Table 2
Neuropsychological Tests Mean Z Scores
NCI Classification Criteria

Neurocognitive impairment was operationally defined using the three recently published
diagnostic methods as previously outlined.57
Statistical Analysis
Demographic and clinical characteristics were summarized with descriptive statistics
including mean (standard deviation) for continuous variables, and frequencies for
categorical variables. One-way analysis of variation (ANOVA) compared patient and
control groups on continuous demographic variables (i.e., age) as well as test- and
domain-based standardized neurocognitive scores, using a Bonferonni corrected alpha
level (p < .002-individual test scores; p<.007 domain scores). Pearsons chi-squares for
parametric data results were determined for comparisons of categorical variables (i.e.,
impairment, intellectual categories). As there were small numbers of subjects enrolled,

we utilized parametric and nonparametric models in the analyses. All analyses were
performed using the Statistical Package for the Social Sciences (SPSS) version 19.
Go to:
Results
Demographics Patient sample
Fifty cSLE patients provided informed consent and 44 completed testing. Six patients
either failed to show up for multiple appointments, or voluntarily withdrew consent
because of lack of time required to complete the testing. Data from three individuals were
eliminated from the final sample due to disclosure of pre-existing co-morbidities (e.g.,
cerebral palsy, longstanding learning issues) after testing was complete. Table 1 outlines
ethnic and socioeconomic status of the participants. Subjects ranged in age from 10 to 21
years, the majority were female, and of Hispanic ethnicity. The cSLE patients reported
significantly lower quality of life as measured by the PedsQL, and a trend towards more
depressed symptoms than the control subjects. Mean full scale estimated intelligent
quotient (IQ) scores were within the average range for both patient and control groups.
Table 1
Baseline Demographics
Comparison to Normative Test Standardization Means

As shown in Table 2, mean standardized test scores for the cSLE subjects were lower
than standardized normative values (Z = 0; SD = 1) for three individual tests (CTMT 1
and 5, Purdue Pegs bilateral hand co-ordination) and one domain (psychomotor speed),
p<0.001 for each. In comparison to normative estimates of low scores, our sample had a
significantly higher proportion of individuals meeting score cutoffs of more than 1 SD
(56.1% versus 16%, p <.0001), 1.5 SD (14.6 % vs 7%, p < .01), and 2 SD (7.3% versus
2%, p <.01).
Comparison to Matched Control Sample
There were no significant differences between cSLE patients and the control sample on
any of the mean standardized individual test scores or the mean aggregate domain scores
(Table 2).
Differential Criteria for NCI

As shown in Table 3, 34.1% of cSLE subjects were classified as cognitively impaired
according to Method 1 criteria. Using Method 2, 14.6% fulfilled criteria for cognitive
decline, and 7.3% fulfilled criteria for cognitive impairment. Finally, using Method 3,
63.4% of cSLE subjects were categorized as cognitively impaired. There were no
significant differences in the proportion of impaired subjects in the cSLE and control
groups using any of the three methods. Overall, Method 3 categorized significantly more
participants as being cognitively impaired than Methods 1 and 2 (p < .0001).
Table 3
Cognitive Impairment Comparison by Different Categorization Methods
NCI Classification and Disease Indices

We observed no significant differences in disease duration, disease activity (SLEDAI) or
damage (SDI) scores between impaired and non-impaired groups, as shown in Table 4.
However, disease activity was generally higher in the NCI group, but this difference did
not reach statistical significance. The proportion of all patients with positive lupus
anticoagulant (LAC, 15%), anti-cardiolipin (ACL, 42%) antibody status or renal disease
(49%) also did not differ by NCI categorization methods.
Table 4
Disease Indicators by Neurocognitive Impairment
NCI and Psychosocial Indices

A self-administered depression index (BDI) and quality of life index (PedsQL) failed to
differentiate between the NCI and unimpaired groups using Method 1 or 2. Using Method
3 criteria, patients in the NCI group reported significantly lower estimates of quality of
life compared to the unimpaired group (Table 5). NCI was not associated with household
income using any of the categorization methods (data not shown).
Table 5
Depression and Quality of Life by Cognitive impairment
NCI and Intellectual Ability

Following previous psychometric methodology for comparing prevalence of low scores
by intellectual level,29 the cSLE subject group was stratified into individuals with average
range intellectual scale scores (IQ 90 standard score, n = 31) and those with below
average scores (IQ 89, n = 10). As shown in Figure 1, patients with below average
intelligence had significantly more test scores more than 1 and 1.5 SD below the mean
than patients with average or above intelligence (>1SD: 7.2 versus 4.4 tests, p < .01; >1.5
SD: 3.4 vs. 2.0 tests, p <.05). However, no differences were observed in the number of
domain scores more than 1, 1.5 or 2 SD below the mean by using this IQ cutoff (>1SD:
0.4 versus 0.06; >1.5 SD: 0.2 versus 0.1; >2 SD: 0.90 versus 0.55, p=NS for all).
Intellectual functioning did not differentiate either the number of tests or domains falling
below any of the three cutoff criteria. Similar results were observed for the control
sample (data not shown).
Figure 1
Test Results by Intelligence Level
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Discussion
Using three different methods for categorizing NCI in cSLE, the prevalence of NCI
among our sample ranged from 7.3% to 63.4%. Perhaps most importantly, test and
domain scores as well as NCI prevalence estimates did not differ between cSLE patients
and controls. Furthermore, these three categorization methods did not relate to measures
of disease activity or damage. However, using the third method,7 NCI was associated
with poorer perceived quality of life, consistent with previous research.3034
The criteria outlined in Method 3 (two or more single tests > 1.5 SD below mean
spanning two different domains) demonstrated the largest number of patients as impaired
(>63%), consistent with the original authors findings in their cohort.7 This is not
surprising, given its inclusion of single test scores in the operational definition and the
psychometric reality that impaired performance on one or more tests in test batteries with
greater than 20 measures occurs in the majority of cognitively healthy subjects.35 The
measurement criteria outlined in Methods 1 and 2 were more moderate estimates of NCI,
each categorizing impairment in approximately one quarter to one third of our sample, a
lower prevalence than the original study (59%).5 Both classification methods uphold the
common criterion of a domain score more than two standard deviations below the mean
and also use secondary criteria to capture individuals who have less severe cognitive
deficits (between 1 and 2 SD below the mean). However, we caution researchers and
clinicians in using the term cognitive decline (as in Method 2) for studies similar to
ours that assess a cross-sectional cohort and do not evaluate for an objective change in
neurocognitive function over time.
Although disease activity has been linked to neurocognitive outcomes in SLE,3640 we did
not observe any association between disease duration, age at diagnosis, disease-related
damage, or potential risk factors including antiphospholipid antibodies or renal disease
and NCI as assessed by any of the three methods, although our small sample size may
have limited our power to detect these associations. Poorer quality of life was associated
with the more inclusive neurocognitive impairment defined in Method 3 and suggests the
potential importance of employing greater leniency in our definitions of impairment, as
well as accounting for the interrelations between mood and cognitive issues prevalent in
this population.4145
Our sample of predominantly adolescents demonstrated neurocognitive deficits in
domains previously proposed to be associated with SLE particularly in the areas of
executive functioning (mental flexibility), psychomotor and fine-motor speed.42,4650 This
is consistent with proposed pathogenetic mechanisms in SLE, highlighting
microstructural white matter changes, particularly in the frontal lobe, potentially
explaining attentional and executive dysfunction as well as motor issues.51 Despite the
salience of these deficits, cognitive interventions have rarely been evaluated in cSLE.52 In
addition to educational accommodations for patients (e.g., direct instruction,
modifications to environmental and task demands), specific interventions for attention
problems caused by poor executive functioning are important and necessary new
directions for cSLE research.
Our study also draws attention to the large number of test scores in the impaired range
according to the different cutoffs, beyond those anticipated using normal curve estimates,
and greater than projected base rates of abnormal scores compared to typically
developing children. Although base rates of low scores are not available for this specific
neuropsychological battery, one recent study demonstrated one or more scores >1 SD in
37.6% of the standardization sample for the Childrens Memory Scale, compared to 56%
of our sample meeting this impairment cutoff across all our domains.29 Further
consideration of the number of low scores found among healthy youth on the
recommended pediatric cSLE test battery and the intercorrelations among these tests is
strongly advised to guide future definitions of NCI within the cSLE population.
Although cSLE patients demonstrated difficulties on individual neurocognitive measures
and domains, they did not demonstrate deficits in excess of control participants, nor were
there any differences between the two groups in any of the three categorizations systems
for NCI. The similarities in low scores and NCI among our patients and healthy controls
suggests overall neurocognitive difficulties in this sample, and questions if poor
performance can or should be attributed to SLE. These findings highlight the importance
of using an appropriate control group when examining NCI in demographically diverse
populations. Use of matched control groups attempts to remedy test norms that may not
reflect the diversity of socioeconomic or ethnic background among medical populations
such as cSLE, a disease with greater prevalence in nonwhite populations. In the past,
failure to use a matched control group has led to a disproportionate number of individuals
to be classified as impaired.50,5356 However, some of the tests used in this study employ
normative samples with increased representation of diverse cultures. For example, the
Weschler intelligence and DKEF tests have samples that include up to 25 percent of
individuals of Hispanic origins,19,21,26 suggesting that our cohort (both patients and
controls) may be unique, with a higher prevalence of NCI than would be expected in a
control population based on available population norms. Our sample represents a
predominantly urban population of lower socioeconomic status, and as such, subjects
may have had fewer educational opportunities than other cSLE samples. Overall, there
were few subjects in the higher household income groups, although analysis did not show
fewer cases of NCI in these higher income strata. Although recruiting friends as a
comparison group controls for important sociodemographic factors including age,
ethnicity, school quality, and household income, the lack of cognitive differences among
our sample may reflect how individuals seek out similarly able or challenged peers for
friendships. Similarities can also be attributed to our cross-sectional methodology, as
previous investigators show comparability between cSLE patients and controls early in
the disease, but slower acquisition of skills and increased cognitive impairment over
time.57
To interpret neurocognitive performance in the context of overall level of intellectual
functioning, we observed that approximately 25% of cSLE patients fell in the below
average intellectual group (IQ 89). However, below average intellect did not
differentiate the number of cognitive domains scoring below 2 SD of the mean, indicating
how few subjects in both our patient and control sample met this level of impairment
criteria. The number of domains and tests more than 1 and 1.5 SD below the mean did
differ by intelligence level, again suggesting more leniencies in standard impairment
criteria. Although examining different test scores by dichotomizing IQ can be
controversial, given the strong correlation between IQ test scores and other
neurocognitive measures, it is also important to account for differential expectations of
below average scores and potential patterns of impairment that may be specific to this
disease process.29,35,58 For example, a person who is lower functioning cognitively will
have more low scores, and be at greater risk for misdiagnosis of NCI (i.e.,false positives),
than a person who is higher functioning (and at greater risk of having a missed diagnosis,
i.e.,false negatives).29 Overall it remains essential to assess the impact of disease on all
neurocognitive domains, including intellectual indices and to acknowledge the additional
challenges inherent in assessing NCI in cSLE patients whose cognitive skills are not yet
fully developed.
Several limitations of the present study should be noted. Most saliently the small sample
size limited the statistical power of our analyses. Our predominantly Hispanic sample
with limited inclusion of other sociodemographic groups also restricts generalizability to
other more diverse cSLE populations. As with many neurocognitive cSLE studies, this
battery of neuropsychological tests was different than previous studies, yielding a
different number of single test scores and reflective of slightly different domains. After
the initiation of this study, a recommended test battery for cSLE was published,
addressing the necessity for pediatric specific instruments, as well as sensitivity for
children with multiple limitations.4 Although our study used many of the same as well as
comparable tests, we recommend that future research follow published guidelines as a
minimum to permit increased comparability across studies. Finally, our study does not
elaborate on the causality of NCI, beyond our examination of disease characteristics, or
examine any potential neuroanatomical differences among our sample.
Despite these limitations, by comparing existing criteria for NCI among cSLE patients in
the same sample, our study controls for previous variability in differential
neuropsychological measures and methodological differences in recruitment in assessing
NCI. Our results highlight the challenges of accurately dichotomizing neurocognitive
impairment generally and more specifically in a disease such as cSLE, known for its
diversity in presentation and impact. Further consideration and refinement of the concept
of NCI among children with SLE is needed. Future efforts are encouraged to go beyond
dichotomous ranking systems and to continue to consider intelligence as well as other
functional outcomes. Overall, consistent use of a single definition in research studies
using similar test batteries based on these considerations will provide further data for
assessment of impairment criteria. Our results suggest the importance of using domain
based scores and flexibility in cutoff criteria between 1 and 1.5 SD below the mean, given
how few individuals met > 2 SD thresholds. Further, addressing the cumulative number
of impaired domains and addressing which neurocognitive processes these represent may
be most valuable in elucidating the underlying neuropsychological networks associated
with cSLE. We are currently testing this in a new multi-ethnic sample to further consider
and expand upon these issues; as well as to consider potential cognitive intervention in
this population. Importantly, no definition should be used in an all or nothing manner
for decision of when to pursue educational assistance and closer follow-up. We remain
optimistic that future multi-centre studies using common methodology and assessment
batteries will be able to accomplish these goals and provide valuable insight into
neuropsychological development and quality of life among children and adolescents with
SLE.
Significance
Although cSLE patients demonstrated difficulties on individual neurocognitive

measures and domains, they did not demonstrate neuropsychological deficits in
excess of control participants, highlighting the importance of using an appropriate
control group when examining NCI in demographically diverse populations.
It is challenging to accurately dichotomize neurocognitive impairment in cSLE, as
categorical classification (i.e. impaired/nonimpaired) oversimplifies the
commonly observed deficits in childhood-onset SLE.
Innovation
cSLE patients are affected particularly in the areas of executive functioning

(mental flexibility), psychomotor and fine-motor speed, suggesting future studies
focus on methodologies to overcome these difficulties.
Go to:
Acknowledgments
DML was supported by NIH/NIAMS grant K23AR053202, CTSA Clinical Scholars
Award from Columbia University, and Pfizer Scholars Grant in Clinical Rheumatology
Go to:
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Jurnal 10
Arthritis Care Res (Hoboken). Author manuscript; available in PMC 2013 July
23.
Arthritis Care Res (Hoboken). 2011 June; 63(6): 884890.
doi: 10.1002/acr.20447
PMCID: PMC3719846
Using the Center for Epidemiologic

Studies Depression Scale to Screen for
Depression in Systemic Lupus
Erythematosus
Laura J. Julian, PhD, Steven E. Gregorich, PhD, Chris Tonner, MPH, Jinoos
Yazdany, MD, MPH, Laura Trupin, MPH, Lindsey A. Criswell, MD, MPH, ED Yelin,
PhD, and Patricia P. Katz, PhD
The publisher's final edited version of this article is available at Arthritis Care
Res (Hoboken)
Go to:
Abstract
Objective
Identifying persons with systemic lupus erythematosus (SLE) at risk for depression
would facilitate the identification and treatment of an important comorbidity conferring
additional risk for poor outcomes. The purpose of this study was to determine the utility
of a brief screening measure, the Center for Epidemiologic Studies Depression Scale
(CES-D), in detecting mood disorders in persons with SLE.
Methods
This cross-sectional study examined 150 persons with SLE. Screening cut points were
empirically derived using threshold selection methods, and receiver operating
characteristic curves were estimated. The empirically derived cut points of the CES-D
were used as the screening measures and were compared to other commonly used CES-D
cut points in addition to other commonly used methods to screen for depression.
Diagnoses of major depressive disorder or other mood disorders were determined using a
gold standard structured clinical interview.
Results
Of the 150 persons with SLE, 26% of subjects met criteria for any mood disorder and
17% met criteria for major depressive disorder. Optimal threshold estimations suggested
a CES-D cut score of 24 and above, which yielded adequate sensitivity and specificity in
detecting major depressive disorder (88% and 93%, respectively) and correctly classified
92% of participants. To detect the presence of any mood disorder, a cut score of 20 and
above was suggested, yielding sensitivity and specificity of 87% and correctly classifying
87%.
Conclusion
These results suggest the CES-D may be a useful screening measure to identify patients
at risk for depression.
Go to:
INTRODUCTION
In 1999, the American College of Rheumatology (ACR) Ad Hoc Committee on
Neuropsychiatric Lupus developed a nomenclature system for neuropsychiatric
syndromes in systemic lupus erythematosus (SLE) (1), which included depressive
disorders of at least moderate severity. The Center for Epidemiologic Studies Depression
Scale (CES-D) was also suggested by this committee as the preferred screening method
for depression in SLE. Despite this recommendation and widespread use of the CES-D,
to our knowledge, no studies have evaluated the psychometric utility of this measure in
persons with SLE.
Depression is a common and debilitating comorbidity associated with SLE (2,3). Quickly
identifying patients with sufficient depressive symptoms requiring treatment or referral to
specialty care is an ongoing challenge in the clinic, particularly with overlapping somatic
symptoms common to both SLE and depression. Conventional methods considered to be
the gold standards for diagnosing depressive disorders are lengthy, require highly trained
evaluators, and are typically unavailable and/or prohibitively costly in the medical
setting.
The primary goal of this study was to determine the utility of the CES-D as a screening
instrument for depression in a cohort of persons with SLE. Specifically, we proposed
using threshold selection techniques to empirically derive cut points of the CES-D in
comparison to traditionally utilized cut points, other commonly used single-item
measures for depression, and questions embedded in other disease activity scales and
quality of life scales, for detecting mood disorders as determined by a gold standard
structured clinical interview (4).
Go to:
SUBJECTS AND METHODS

Subjects and data collection method
The sample for this study was drawn from participants in the University of California,
San Francisco Lupus Outcomes Study (LOS), a prospective study of 957 individuals with
diagnostically confirmed SLE (by medical chart review using ACR criteria) (5). Details
about enrollment and data collection for this study have been reported previously (6), and
are briefly summarized here. Subjects were recruited through academic medical centers
(25%), community rheumatology offices (11%), nonclinical sources, including patient
support groups and conferences (26%), and other various forms of the media (38%). The
primary data collection method was through annual telephone interviews. Participants
who live in the greater San Francisco Bay area were recruited for an in-person assessment
in the Clinical and Translational Science Institutes Clinical Research Center (CRC) for a
comprehensive clinical study evaluating depression, body composition, physical function,
and disability. Exclusion criteria for this larger study included non-English speaking,
younger than age 18 years, 50 mg or greater of oral prednisone, pregnancy, uncorrected
vision problems interfering with reading ability, and joint replacement within the past
year. Three hundred twenty-five individuals were asked to participate; 74 (22.8%) were
ineligible (35 lived too far away, 25 were too ill, 9 had had recent surgery, 2 were
pregnant, 2 had poor English skills, and 1 had cognitive problems). Of the 251 eligible
individuals, 84 (33.5%) declined participation. Reasons for declining were primarily
related to transportation (n = 12) and scheduling difficulties (n = 39). One hundred sixtythree individuals completed the study visits. Complete data were achieved in 150 persons.
This research protocol has been approved by the University of California, San Francisco
Committee on Human Research. All participants gave their informed consent to
participate.
Sociodemographic and disease characteristics
Sociodemographic factors
Sociodemographic characteristics included age, sex, race/ethnicity, education (college
education versus less than college educated), marital status (married/with partner versus
not), employment status (currently working versus not), and poverty status (household
income at or below versus above 125% of the federal poverty threshold).
Sociodemographics were collected through the LOS telephone interview.
Health and disease characteristics

Disease activity was assessed using the Systemic Lupus Activity Questionnaire (SLAQ),
a validated, self-report measure of disease activity in SLE that includes items assessing
constitutional symptoms, mucocutaneous symptoms, musculoskeletal symptoms, and
other disease activity domains (7,8). A modified SLAQ was also calculated, excluding
symptoms overlapping with depression (i.e., depressed mood, concentration problems,
and decreased energy). Other disease characteristics included disease duration (years),
current treatment with glucocorticoids, mean corticosteroid (prednisone) dose, suspected
renal involvement (i.e., reported an abnormal urinalysis, including blood or protein in
urine), and reported history of stroke or myocardial infarction. Finally, the Medical
Outcomes Study Short Form 36 (SF-36) physical function scale was utilized as a general
measure of physical limitations (9). With the exception of information about medications,
which was collected at the CRC, all health and disease characteristics were collected in
the telephone interview. The mean SD interval between assessment of health and
disease characteristics and the assessment of depression was 3.3 3 months.
Depression measures
CES-D
The CES-D (4) was used in this study as the screening measure of depression and was
administered in questionnaire form at the CRC visit. The CES-D is a 20-item scale
commonly used to evaluate current depressive symptom severity, with a score range of 0
60 (higher scores reflect increased symptom severity). Item responses range from 0 to 3,
where 0 = rarely or none of the time (less than 1 day in the past week), 1 = some or a
little of the time (12 days), 2 = occasionally or a moderate amount of the time (34
days), and 3 = most or all of the time (57 days). The CES-D was recommended by the
ACR Ad Hoc Committee on Neuropsychiatric Lupus as the preferred measure of
depressive symptom severity for patients with SLE (1). Empirically derived cut scores
will be compared to conventional cut scores of 16 and 23 (10). Previous studies have also
suggested a cut score of 19 for rheumatoid arthritis, using a 13-item modification of the
CES-D removing somatic items (11). We also compared our empirically derived cut
scores to this 13-item modification to determine performance in comparison to other
validation studies in rheumatic disease.
Mini-International Neuropsychiatric Interview (MINI)

The MINI (12) was utilized as the gold standard to determine the presence versus absence
of either current major depressive disorder or any mood disorder, including dysthymia,
minor depression, and major depressive disorder. The MINI was designed as a structured
interview to determine diagnoses for the major axis I psychiatric disorders in the
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and the
International Statistical Classification of Diseases and Related Health Problems, Tenth
Revision (ICD-10). Validation and reliability studies have been conducted comparing the
MINI to the commonly used Structured Clinical Interview for the Diagnostic and
Statistical Manual of Mental Disorders, Third Edition, Revised and the Composite
International Diagnostic Interview (a structured interview developed by the World Health
Organization for lay interviewers for ICD-10) (12), with results indicating that the MINI
has acceptably high validity and reliability scores. The MINI has been used in a range of
conditions, including rheumatologic populations (13). Evaluators at the CRC were trained
to conduct the MINI along with standardized clinically informed prompts by a licensed
clinical psychologist (LJJ) in 14 training days over the course of 4 weeks, including
assessments observed by the trainer. Results for all patient interviews were reviewed for
proper diagnostic conclusions. On average, the MINI administration is 1525 minutes.
The MINI was administered at the CRC at least 1 hour after administration of the CES-D
by an evaluator blinded to the results of the CES-D.
Depression screening measures used for comparison

Single- or 2-item measures have been shown to be equally useful as longer questionnaires
in screening for depression (14). Additionally, mood items are often embedded into other
measures of disease status and quality of life, and the degree to which the CES-D may
perform better than these measures is not known. In order to test the utility of the CES-D
in comparison to these single-item and quality of life approaches, we used the following
measures: 1) embedded single-item mood question: as part of the SLAQ (7,8), all
participants were asked, Over the past three months, has depressed mood been a
problem for you, which yielded a dichotomous (yes versus no) response, and 2) subscale
embedded in a quality of life questionnaire: the SF-36 mental component score was used
and a cut score of 29 and below was used as an index of clinically significant mood
problems, as suggested in previous studies (15).
Statistical analyses
Descriptive statistics were used to characterize participant sociodemographics and
disease status. To determine the optimal screening cut point of the CES-D for major
depressive disorder and any mood disorder, receiver operating characteristic (ROC)
curves were estimated and two threshold selection methods were utilized: the Youden
Index and a second technique that determines the proximity to perfect correspondence
(referred to in this article as a Distance to Perfect Index) (16). Briefly, the Youden
Index determines the maximum vertical distance from the ROC curve to the diagonal
reference, or chance line, i.e., the optimal cut point corresponds to the point on the
ROC curve farthest from the reference line, which has previously been used as a measure
of the accuracy of a diagnostic test in clinical epidemiology (17). Similarly, the Distance
to Perfect Index selects the point on the ROC curve that is closest to the upper left-hand
corner of the graph (0,1), representing perfect classification (18), thereby minimizing
misclassification. Cut points were initially determined for the entire sample and
compared to traditionally suggested CES-D cut points, the somatic itemfree CES-D,
responses of yes to the two single-item measures, and a score of 29 and below on the
SF-36 mental component score.
Go to:
RESULTS
Sociodemographic and health-related characteristics of the cohort are shown in Table 1.
Participants had a mean SD age of 48.8 12.3 years, 93% were women, 63% were
white, 69% had a college degree, and 12% had poverty-level household incomes (<125%
of the federal poverty threshold). The mean SD disease duration was 15.8 9.3 years,
the mean SD SLAQ disease activity score was 12.1 7.1, 42% reported recently
having suspected renal involvement, and 16% had a history of stroke or myocardial
infarction. According to the MINI diagnostic criteria, any mood disorder was present in
26% of the sample (Table 1), with major depressive disorder as the most prevalent
disorder (17%), followed by minor depression (6%) and dysthymia (4%). Two
individuals met criteria for major depressive disorder and dysthymia (1%).
Table 1
Systemic lupus erythematosus patient characteristics *
ROC curves are shown in Figure 1. Results from the Youden and Distance to Perfect
indices were somewhat disparate for a diagnosis of major depressive disorder. The
Youden Index derived a cut score of 21 with a sensitivity, specificity, positive predictive
value, and negative predictive value of 96%, 85%, 58%, and 99%, respectively. The
Distance to Perfect Index derived a higher cut score of 24 with a sensitivity, specificity,
positive predictive value, and negative predictive value of 89%, 93%, 72%, and 98%,
respectively. Given these results, an optimal cut point of 24 was selected due to the
slightly favorable balance between sensitivity and specificity, and the improved positive
predictive value (Table 2). To detect cases of any mood disorder, the indices both
suggested that the optimal CES-D cut point was 20 and greater, with a sensitivity,
specificity, positive predictive value, and negative predictive value of 87%, 87%, 69%,
and 95%, respectively (Table 3). Psychometrics were not substantially different when
patients were stratified by race/ethnicity (white versus nonwhite) (results not shown).
Figure 1
Receiver operating characteristic (ROC) curves for the Center for
Epidemiologic Studies Depression Scale (CESD) in predicting a diagnosis of
mood disorders in systemic lupus erythematosus.
Table 2
Sensitivity and specificity of traditionally utilized CES-D cut points and
empirically derived cut points in systemic lupus erythematosus for a
diagnosis of major depressive disorder *
Table 3
Sensitivity and specificity of traditionally utilized CES-D cut points and
empirically derived cut points in systemic lupus erythematosus for a
diagnosis of any mood disorder*
Empirically derived cut points for a diagnosis of major depressive disorder are shown in
Table 2 with traditionally utilized cut scores of the CES-D, the modified somatic-free
CES-D score, and our other two comparison measures (one single-item measure and the
mental component score of the SF-36). In these analyses, the empirically derived CES-D
cut point yielded the highest overall classification rates (92%). According to McNemars
exact test, although threshold analyses suggested a cut point of 24 as optimal, this cut
point was not statistically different than a CES-D cut point of 23 (P = 0.12).
Likewise, the empirically derived cut point of 20 for a diagnosis of any mood disorder
along with comparison measures are shown in Table 3. This cut point of 20 performed
very similarly to a commonly used cut point of 23 with a slightly increased sensitivity,
suggesting there is little differentiation between these two points in detecting a diagnosis
of any mood disorder.
Finally, empirically derived cut points for the CES-D in detecting major depressive
disorder and any mood disorder were compared to a single-item measure of depression
and the mental health component score of the SF-36. Threshold analyses suggested a cut
score of 40 and below for the mental health component score for detection of major
depressive disorder, and 44 and below for detection of any mood disorder. In both cases,
the CES-D cut scores had improved classification rates (Tables 2 and and33).
Go to:
DISCUSSION
The purpose of this investigation was to determine the utility of the CES-D screening
instrument for depression among persons with SLE. In this sample, 17% of persons met
criteria for major depressive disorder and 26% met criteria for any mood disorder,
including major depressive disorder, minor depression, and dysthymia, using a
comprehensive structured clinical interview from the DSM-IV. To our knowledge, the
present study is one of few studies employing structured clinical interview techniques for
depression. Notably, prevalence rates from our study were similar to a previous study
using comparable (DSM-IV based) interview techniques (19). In this comparable study of
women with SLE, Nery and colleagues found mood disorders present in 27% and a
diagnosis of major depressive disorder in 22% (19). Results of the threshold estimation
techniques suggested a cut point score of 24 and above on the CES-D, which correctly
classified 92% of participants as current major depressive disorder present versus absent.
Overall, the CES-D appears to be a useful screening measure to identify patients who
have a range of disease activity levels to detect the presence of major depression.
This proposed cut score of 24 is very similar to the commonly used cut score of 23 for
probable depression (10) and may have some improved psychometric properties, but
was not statistically different. Our results suggest that in this disease population, a higher
cut score may be advantageous in identifying patients who likely meet criteria for major
depression. This cut score of 24 is also similar to a recently suggested cut score of 25 for
older adults (20).
We also investigated the utility of the CES-D for detection of any mood disorder,
including major depression, minor depression, and dysthymia. To detect any of these 3
mood disorders, the threshold estimation techniques suggested a cut point score of 20 and
above, which was observed to yield optimal diagnostic accuracy. Although our
classification of any mood disorder is heterogeneous and represents a broad category of
mood disorders, sensitivity and specificity remained reasonably high at 87% for both.
These results suggest that the CES-D may also be useful for the detection of this broad
category of mood disorders, including subsyndromal depression. Using the CES-D to
detect patients at risk for a range of mood disorders may be a useful approach,
particularly to identify those with subsyndromal depression. Subsyndromal depressive
symptoms not meeting criteria for a depressive disorder have been observed to place
patients at risk for poor outcomes (21). Therefore, monitoring those patients who endorse
these symptoms of depression more closely in the course of clinical care may be
warranted.
It is well understood that assessing depression in a medical population presents specific
measurement challenges. One of the most prominent of these challenges is the issue of
symptom contamination. Clearly somatic symptoms of depression overlap with diseaserelated symptoms, particularly decreased energy, concentration difficulties, sleep, and
appetite disturbance. Empirical methods have been previously employed to address this
problem by removing contaminating items (22), or in selecting measures that are
relatively somatic symptom free (e.g., the Geriatric Depression Scale). In our study, we
compared our empirically derived cut scores to a comparably derived cut score on the
modified somatic symptomfree measure previously suggested for use in rheumatoid
arthritis. These results suggest that by removing the somatic symptoms, we may not be
improving detection of depressive disorder in this condition, and in some instances the
cut score derived from the original CES-D performed better than a modified version.
Overall, we believe that the unmodified CES-D may be useful and has the advantage of
maintaining the psychometric integrity of the measure. Maintaining the original item
structure facilitates broad use of the CES-D in SLE and enables comparisons across
populations. Furthermore, while there is certainly the potential of overlapping symptoms
causing inflation of depression severity scores and thereby shifting base rates of
depression in populations, this potential relies on the assumption that these somatic
symptoms of depression are invariably etiologically linked to the medical condition. It is

equally possible that these somatic symptoms of depression are etiologically linked to an
underlying depressive disorder (23), and removing these symptoms may underestimate
the prevalence and severity of depression. Recently, Thombs et al observed that somatic
symptoms were not endorsed at substantively higher rates by scleroderma patients
compared to matched community controls, further supporting this idea (24). In this study,
we cannot ascribe the etiology of our somatic symptoms. However, it is important both in
the clinical and research setting to remain cognizant of these issues, and future
longitudinal studies tracking the evolution of these symptoms in SLE are warranted.
Limitations of this study include the potential for reduced generalizability. First, healthier
individuals may be more likely to participate in this study, particularly since it required
travel to our CRC. However, the prevalence of significant disease manifestations in this
cohort suggests that disease severity may be representative of persons with SLE. Second,
we included only English-speaking patients, limiting the generalization of our results to
non-Englishspeaking patients with SLE. Third, with the exception of SLE diagnostic
status, health characteristics are collected by self-report. It is possible that our patients are
unaware of their health status across all factors. Fourth, the sample sizes of participants
who met criteria for depression are relatively small, and further psychometric
confirmation is warranted in a larger sample. Fifth, although the CES-D is easily
administered and scored, it is also somewhat longer (i.e., 20 items) than other depression
scales (e.g., the Patient Health Questionnaire 9 [PHQ-9] [25]). There is increasing
reliance on these briefer measures, yet psychometric evaluation of these briefer measures
needs to be completed in complex conditions such as SLE. For example, although the
PHQ-9 has been shown to be associated with the CES-D in rheumatic disease (26), the
PHQ-9 was not validated against a structured clinical interview for mood disorders. In
addition, we compared the CES-D to a single-item measure that may lack sensitivity
compared to other established ultra-short measures previously studied (27). Furthermore,
there is the potential for spectrum bias in that we included patients who were potentially
being treated for depression in this sample, and therefore there may be some increase in
our estimates of diagnostic accuracy. Finally, although the screening and the gold
standard depression measures were both evaluated at the same visit, disease
characteristics, quality of life, and the single-item question were evaluated by the
preceding LOS telephone interview, and it is possible that symptoms and some aspects of
disease activity may have changed between the telephone interview and their CRC visit.
Depression is a common and debilitating comorbidity associated with SLE. Results from
this study suggest that the CES-D, which is quickly administered and easily scored, may
be a useful tool in the research and clinical setting to identify depression among persons
with SLE. In the clinic, it is important to highlight that screening for depression is only
one aspect of appropriate care in both primary care and subspecialty clinics. One
potential disadvantage for depression screening is the possibility of opportunity cost, in
that even a relatively brief screen for depression could detract from screening and
assessment of other clinical issues. Second, merely screening for depression may not be
beneficial in the absence of a comprehensive care model with adequate resources for not
only assessment, but also treatment and followup (28). Randomized clinical trials are
necessary in SLE and other rheumatic diseases to fully understand the benefitharm
tradeoffs for screening for depression in the context of specialty care.
In sum, depression in the context of SLE, like many chronic conditions, is a substantial
risk factor for a number of poor health outcomes, including decreased treatment
adherence and increased disability (28,29). Additionally, mental health status is among
the strongest predictors of health care costs among patients with SLE (30). A number of
effective treatments for depression are available and identifying patients at risk for
significant depressive disorders in the context of a comprehensive care model could
substantially improve the quality of life for patients with SLE.
Go to:
Acknowledgments
Supported by the NIH/National Center for Research Resources University of California,
San Francisco Clinical and Translational Science Institutes (grant UL1-RR024131), the
NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants P60AR053308 and K08-MH072724), and The Rosalind Russell Medical Research Center for
Arthritis.
Go to:
Footnotes
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it critically for
important intellectual content, and all authors approved the final version to
be published. Dr. Julian 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 conception and design. Julian, Gregorich, Katz.

Acquisition of data. Julian, Criswell, Yelin, Katz.
Analysis and interpretation of data. Julian, Gregorich, Tonner, Yazdany, Trupin, Yelin,
Katz.
The contents of this article are solely the responsibility of the authors and do not
necessarily represent the official views of the NIH.
Go to:
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Aspek Psikiatrik Pada Penderita SLE

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Aspek Psikiatrik Pada Penderita SLE

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Aspek psikiatrik pada penderita SLE

The Correlations of Disease Activity,

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that

2. Patients and Methods

2.2. Measures of Clinical Variables

2.3. The Revised Self-Rating Anxiety Scale (SAS) [19]

2.4. The Revised Self-Rating Depression Scale (SDS) [20]

2.5. Measure of the Quality of Life [21]

2.6. Statistical Analysis

3.2. Correlations between Psychological Scores, Disease Parameters, and

3.3. Stepwise Regression Analysis for Anxiety and Depression

importance of psychosocial interventions in combination with medical therapy for SLE

Prevalence and predictors of depression

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which usually

Material and methods

included in multiple linear regression analysis as independent variables. Moreover, other

2. Jewett LR, Razykov I, Hudson M, Baron M, Thombs BD, on behalf of the

Validity of LupusQoL-China for the

Therefore, attention has been turned toward developing a more disease-specific

Patients and Methods

EuroQoL Scale (EQ-5D)

Internal Consistency Reliability

perfectly understandable and conceptual equivalence of the source. We piloted a

Chinese attitude toward sexual intercourse. Traditional concepts in Chinese culture

6. Sullivan PW, Ghushchyan V (2006) Preference-Based EQ-5D index scores

22. Daleboudt GM, Berger SP, Broadbent E, Kaptein AA (2011) Health-related

Discoveries in the pathophysiology of

Systemic lupus erythematosus (SLE) is a multi-system inflammatory disorder

Neurological effects of the 16/6 Id antibody

The 16/6 Id antibody is a novel antibody contributing to the

Future directions and conclusions

10. Sencal JL, Raymond Y. The pathogenesis of neuropsychiatric manifestations in

J Rheumatol. Author manuscript; available in PMC 2013 April 22.

Association Between Depression and

Author information Copyright and License information

MATERIALS AND METHODS

Traditional cardiovascular risk factors

Vascular disease endpoint

Vascular disease and CVD risk factors

motivation, depression may be a direct consequence of inflammation. However,

Validity of Brief Screening Tools for

To determine the validity of standardized screening assessments of cognitive functioning

Subjects and Methods

Sociodemographic factors, disease characteristics, and depression

Measures of neuropsychological impairment

Screening measures of neuropsychological impairment

Significance & Innovations

The burden of cognitive impairment is high in systemic lupus erythematosus

17. Benedict RH, Brandt J. Hopkins Verbal Learning Test-Revised/Brief Visuospatial

Multimodal neurophysiological and

Patients and methods:

The use of multimodal neuropsychiatric evaluations is essential for diagnosis of early

Patients and methods

Psychosocial dimensions of SLE:

and emotional challenges. Patients often experience a high degree of psychological

Materials and methods

SLE needs questionnaire

Multidimensional health locus of control scale findings

therapeutic approaches, such as crisis intervention and task-centered counseling, to

13. Schattner E, Shahar G, Leman S, Shakra MA. Depression in systemic lupus

Neuropsychological batteries, by definition, employ several tests to assess each of the

Patients and Methods

relevant to the pediatric population. Neuropsychological testing was performed by a

NCI Classification Criteria