Cardiovascular and Disease-Related Predictors of
Depression in Systemic Lupus Erythematosus
LAURA J. JULIAN, CHRIS TONNER, ED YELIN, JINOOS YAZDANY, LAURA TRUPIN,
LINDSEY A. CRISWELL, AND PATRICIA P. KATZ
Objective. Depression and cardiovascular disease are common and debilitating comorbidities associated with systemic
lupus erythematosus (SLE). In this study, history of cardiovascular events, cardiovascular risk factors, and SLE disease-
related factors were evaluated as longitudinal predictors of depression in a large cohort of patients with SLE.
Methods. Data were derived from 663 adult participants in the 2004–2008 Lupus Outcomes Study, who were followed
for up to 5 annual interviews. Multivariate logistic regression analyses using generalized estimating equations were used
to determine predictors of the development of increased depressive symptom severity over a 12-month period (Center for
Epidemiologic Studies Depression Scale [CES-D] score of 23 or greater), yielding 2,224 paired observations. Predictors
included sociodemographics, traditional cardiovascular risk factors (reported presence of heart disease, history of stroke
or myocardial infarction, hypertension, hypercholesterolemia, diabetes mellitus, obesity, smoking status, and family
history), and SLE-specific risk factors (glucocorticoid use, renal involvement, disease duration, and disease activity).
Results. The annual incidence of depression was 12% in this cohort. Multivariate predictors of new-onset depression
included younger age (ages 20–39 years: odds ratio [OR] 2.3, 95% confidence interval [95% CI] 1.3–3.9; ages 40–59 years:
OR 1.8, 95% CI 1.1–2.7), Hispanic/Latino ethnicity (OR 1.8, 95% CI 1.2–2.8), having some college education (OR 1.8, 95%
CI 1.1–3.0), baseline CES-D score (OR per point 1.1, 95% CI 1.1–1.2), presence of diabetes mellitus (OR 1.8, 95%
CI 1.1–2.8), and baseline SLE disease activity (OR 1.2, 95% CI 1.1–1.4).
Conclusion. These results suggest that, in addition to known sociodemographic factors, the presence of diabetes mellitus
and SLE disease activity may play a role in the development of depression in SLE.
Depression is a debilitating comorbidity common among
patients with systemic lupus erythematosus (SLE). Studies
cite a broad range of prevalence rates of depression ranging
from 17–75% (1–7); however, recent estimates suggest that
point prevalence rates of clinically significant symptoms
and lifetime incidence of major depressive disorder occur
in approximately half of patients with SLE (8–11). In 1999,
the American College of Rheumatology (ACR) developed a
nomenclature system for 19 neuropsychiatric syndromes
in SLE (12), which included mood disorders of at least
moderate severity. Since the development of this nomen-
clature system, there has been considerable debate about
the inclusion of depression as a neuropsychiatric SLE
manifestation, and the nomenclature system has been crit-
icized as lacking specificity for SLE-specific central ner-
vous system involvement (13–15). Using decision rules to
estimate the attribution of depression to SLE disease pro-
cesses, studies suggest that mood disorders are as likely to
occur as a result of pathophysiologic SLE processes as
other reasons (psychosocial, impact of disease on quality
of life, etc.) (16,17).
A number of disease-related processes have been con-
sidered as potential etiologic factors contributing to de-
pression in SLE. Specific autoantibodies have been impli-
cated, including anti–ribosomal P autoantibodies (18),
cross-reacting N-methyl-D-aspartate autoantibodies (19),
and antiphospholipid antibodies (20). Additionally, al-
though few studies have evaluated specific markers of
inflammation in relation to depression, a link has been
Because Drs. Katz and Yelin are Editors of Arthritis Care
& Research, review of this article was handled by the Editor
of Arthritis & Rheumatism.
Supported by the National Institute of Arthritis and Mus-
culoskeletal and Skin Diseases (grant P60-AR-053308), the
National Institutes of Mental Health (grant K08-MH-
072724), the Rosalind Russell Medical Research Center for
Arthritis at the University of California, San Francisco, and
the State of California Lupus Fund.
Laura J. Julian, PhD, Chris Tonner, MPH, Ed Yelin, PhD,
Jinoos Yazdany, MD, MPH, Laura Trupin, MPH, Lindsey A.
Criswell, MD, MPH, Patricia P. Katz, PhD: University of
California, San Francisco.
Address correspondence to Laura J. Julian, PhD, Depart-
ment of Medicine, University of California, San Francisco,
3333 California Street, Suite 270, San Francisco, CA 94143-
0920. E-mail: firstname.lastname@example.org.
Submitted for publication April 16, 2010; accepted in
revised form December 15, 2010.
Arthritis Care & Research
Vol. 63, No. 4, April 2011, pp 542–549
© 2011, American College of Rheumatology
SPECIAL THEME ARTICLE: VASCULAR COMORBIDITY IN THE RHEUMATIC DISEASES
observed between overall SLE disease activity, a potential
proxy for inflammation, and depression (21,22). Few stud-
ies have explored the role of cardiovascular disease and
risk in the context of depression in SLE. One such study
observed a cross-sectional relationship between subclini-
cal markers of cardiovascular disease (i.e., coronary artery
calcification) and depression in a well-described SLE co-
hort (23). Another study found an association between the
presence of atherosclerosis and mood disorders in a Rus-
sian cohort of SLE patients (24).
Initially termed “atherosclerotic depression” (25), the
vascular depression hypothesis posits that subclinical
cerebrovascular disease can “predispose, precipitate, or
perpetuate a depressive syndrome” (26). There has been
considerable effort to understand vascular depression as a
potential diagnostic subtype of major depressive disorder,
including clarifying the specific role of cardiovascular and
cerebrovascular characteristics as risk factors for the de-
velopment of depression (26–28). Vascular depression has
been almost exclusively described in older adults as a
substantive cardiovascular/cerebrovascular risk that typi-
cally accumulates later in life. SLE is a condition charac-
terized by strikingly high rates of cardiovascular disease
and cerebrovascular disease in a relatively young popula-
tion (29–31). Despite considerable evidence in the general
population linking cardiovascular disease and risk factors
to depression, relatively few studies have explored these
relationships in SLE.
Cardiovascular disease has emerged as a major cause of
morbidity and mortality in SLE (32,33). Traditional risk
factors for cardiovascular disease, including tobacco use,
hypertension, hyperlipidemia, and obesity, have been ob-
served to occur at higher rates in SLE compared to
matched samples (30,34,35). However, other studies cite
traditional cardiovascular risk factors in SLE occurring
at similar rates when compared to age-matched peers
(30,36). It has become clear that these traditional cardio-
vascular risk factors do not fully explain the cardiovascu-
lar burden observed in SLE (37). Disease- and treatment-
related factors may also be important contributors to the
development of cardiovascular disease (38,39). First,
chronic inflammation is a key pathogenic mechanism for
atherosclerosis and cardiovascular disease in SLE (29,40),
whether measured by specific biologic markers (e.g.,
C-reactive protein level) or when measured by proxy mea-
sures such as disease activity and damage (29,41,42).
Other SLE-related factors include renal involvement
(43,44) and potentially treatment-related factors, including
chronic glucocorticoid use. Glucocorticoid use may be a
reflection of active disease; however, this treatment also
directly contributes to cardiovascular risk and disease (hy-
pertension, diabetes mellitus, increased adiposity, etc.)
The purpose of this study was to explore the role of
traditional (e.g., Framingham-type) cardiovascular and
SLE-specific risk factors as predictors of the longitudinal
development of depression in a large observational cohort
of adults with SLE followed over the course of 5 years. We
aimed to test the impact of traditional and disease-specific
risk factors on the development of incident depression
above and beyond that which can be predicted by socio-
demographic characteristics known to be associated with
depression in the general population. An improved under-
standing of etiologic factors associated with depression in
SLE can point to targeted strategies for both prevention
and intervention of depression.
SUBJECTS AND METHODS
A subset of participants was included in this study from
the Lupus Outcomes Study (LOS), a prospective longitu-
dinal study of 957 individuals with SLE whose diagnoses
were confirmed by medical chart review prior to enroll-
ment using ACR criteria (46). Details about enrollment and
data collection for this study have been reported previ-
ously (47), and are briefly summarized here. Subjects were
recruited through academic medical centers (25%), com-
munity rheumatology offices (11%), and nonclinical
sources, including patient support groups and conferences
(26%) and other forms of media (38%). Initial subject
recruitment occurred between 2002 and 2004; a second
enrollment period began in 2006. Annual retention rates in
the study have consistently exceeded 92%, including mor-
tality. The principal data collection modality is an annual
standardized telephone interview that averages 50 min-
utes in length and consists of validated measures of SLE
disease activity and manifestations, general physical and
mental health status, disability, employment, service uti-
lization, and sociodemographic characteristics. This re-
search protocol has been approved by the University of
California, San Francisco Committee on Human Research.
All of the participants gave their informed consent to be
part of the study.
Dependent variable: depressive symptom severity. The
dependent variable is new-onset “depression” over a 12-
month period. The Center for Epidemiologic Studies De-
pression Scale (CES-D) was used to evaluate depression
status. The CES-D is a commonly used 20-item scale to
evaluate depressive symptom severity, with a score range
of 0–60 (48). A CES-D cut score of ?16 was suggested to
identify individuals with “possible” depression, and a
CES-D cut score of ?23 has been suggested to identify
individuals with “probable” depression (49). This higher
cut score has been consistent with other studies, suggest-
ing that a higher cut score more accurately identifies per-
sons with major depression (48,50,51). Therefore, we de-
fined incident depression as those cases crossing a more
conservative threshold of ?23 to identify patients with
symptoms more consistent with a diagnosis of major de-
pression. Although we recognize that the CES-D is a mea-
sure of symptom severity and not diagnostic status, to
maintain brevity we use the terms “depressed” or “depres-
sion” for patients who meet the CES-D score of 23 and
above in this article.
Independent variables. Sociodemographic factors. So-
ciodemographic characteristics included in this study were
age, sex, race/ethnicity (white, African American, Asian, and
Hispanic/Latino), education (less than high school, high
school, some college, and college educated), and poverty
Predictors of Depression in SLE 543
above 125% of the Federal Poverty Threshold).
Depressive symptom severity. The CES-D total score
was also used as an independent variable in order to
account for baseline levels of depressive symptoms not
meeting the criteria for our definition of depression. In this
case, CES-D severity would range from 0–22, as partici-
pants with a score of 23 or above would be excluded from
a time 1 data point.
History of cardiovascular events and risk factors. The
following cardiovascular events and risk factors were eval-
uated: reported history of heart disease (including angina
and congestive heart failure), myocardial infarction,
stroke, hypertension, hypercholesterolemia, diabetes mel-
litus, obesity (defined as a body mass index ?30 kg/m2),
smoking status (current smoker and ever smoker versus
never smoked), and family history of diabetes mellitus
SLE-specific risk and disease factors. Disease activity
was assessed using the Systemic Lupus Activity Question-
naire (SLAQ), a validated, self-report measure of disease
activity in SLE that includes items assessing constitutional
symptoms, mucocutaneous symptoms, and musculoskele-
tal symptoms, among other disease activity domains
(52,53). Other SLE-related disease characteristics included
disease duration (years), self-reported presence of renal
involvement since the year prior to the beginning of study
participation, and current treatment with glucocorticoids.
Study sample. The present analysis includes data from
interviews conducted between 2004 and 2008, including
participants interviewed for at least 2 consecutive years.
To analyze predictors of incident depression, we created a
unit of analysis consisting of pairs of consecutive observa-
tions, with the independent variables measured as of the
first year of the pair (time 1), and depression status taken
from the second year (time 2), an average of 12 months
later. Therefore, a participant can contribute 1 observation
for every 2 consecutive interviews. If a participant had
CES-D scores ?23 at all of the 5 waves, he or she was
excluded from data analyses, leaving 2,327 observations,
of which an additional 103 (4%) were excluded due to
missing data. An individual excluded from the analysis in
1 paired-year observation due to a time 1 CES-D score of
?23 or missing data could be included in a subsequent
observation if a new time 1 CES-D score of ?23 is present.
The final sample included 2,224 observations among 663
LOS participants, an average of 3.4 observations per LOS
Statistical analysis. First, we ran a univariate model
using generalized estimating equations (GEEs) to fit a lo-
gistic regression model. Next, we ran a series of multivar-
iate models using a GEE that simultaneously fits a logistic
regression model (54). Colinearity thresholds were also
considered. The first model examined the association of
symptom severity (CES-D total score), and new-onset de-
pression. The second model built on the previous model
by adding traditional cardiovascular risk and disease fac-
tors. The final model added SLE-specific risk and disease
factors. All multivariate models include the time 1 CES-D
score, which could vary between 0 and 22 (mean ? SD
8.7 ? 6.3, since observations with a time 1 CES-D score of
23 or greater had already been excluded). We present the
results of these models using odds ratios (ORs) with 95%
confidence intervals (95% CIs).
As a sensitivity analysis, we repeated the series of mul-
tivariate analysis substituting the variable SLAQ (a mea-
sure of disease activity) with a modified version of the
SLAQ. This modified version removes the SLAQ items
that may overlap with our assessment of depression (i.e.,
depressed mood, fatigue, and forgetfulness).
Sample characteristics and bivariate results. Twelve
percent of observations were found to develop “depres-
sion” during the course of this study. Time 1 characteris-
tics for the final sample are depicted in Table 1. The
Table 1. Characteristics of systemic lupus erythematosus
at time 1
(n ? 663)
Living below poverty
High school graduate or less
History of MI or stroke
Body mass index ?30 kg/m2
History of smoking
Recent renal involvement
Disease duration, mean ? SD
Disease activity, mean ? SD
Months from time 1 to time 2,
mean ? SD
14.7 ? 8.7
10.4 ? 6.9
12.6 ? 2.8
* Values are the number (percentage) unless otherwise indicated.
MI ? myocardial infarction; SLAQ ? Systemic Lupus Activity
544 Julian et al
depression characteristics of the 663 participants were as
follows: 467 (70%) never developed depression, 115
(17%) had 1 instance of depression, and 81 (12%) had
more than 1 instance of depression. Univariate observa-
tional analyses of sociodemographics suggest that persons
between the ages of 40 and 59 years, persons with some
college education, and persons who identify their race/
ethnicity as Hispanic/Latino were more likely to develop
depression compared to older adults or younger partici-
pants. The unadjusted analyses evaluating cardiovascular
risk factors and SLE disease factors suggest that those with
heart disease, history of myocardial infarction or stroke,
diabetes mellitus, obesity (body mass index ?30 kg/m2),
glucocorticoid use, renal involvement, a shorter disease
duration, and increased disease activity were also more
likely to develop depression at a subsequent interview com-
pared to persons who remained nondepressed. Colinearity
diagnostics suggested no evidence of shared variance that
would preclude including all variables in the model.
depression are depicted in Table 2. Model 1 included time
1 demographics and depressive symptoms. In this model,
persons with less than a college education (OR 1.8, 95% CI
1.1–3.3) and participants who were Hispanic/Latino (OR
1.8, 95% CI 1.2–2.8) were more likely to become de-
pressed. Time 1 CES-D symptom severity was also a sig-
nificant predictor of new-onset depression (OR per point
1.2, 95% CI 1.1–1.2).
Model 2 incorporated traditional cardiovascular risk fac-
tors in addition to time 1 demographics and depressive
Multivariate analyses predicting
Table 2. Predictors of the development of depression over 1 year (n ? 2,224 observations)*
Multivariate analyses, OR (95% CI)
Model 1Model 2 Model 3
High school graduate or less
Living below poverty threshold
Baseline depression (CES-D score)
Traditional cardiovascular risk and disease
History of MI or stroke
Obesity (body mass index ?30 kg/m2)
History of smoking
SLE-specific disease characteristics
Recent renal involvement
Disease duration, years
Disease activity, SLAQ score (per 5-unit
1.3 (0.7–2.1) 1.1 (0.7–1.9)1.2 (0.7–2.1)1.1 (0.6–1.9)
1.9 (1.3–2.9)1.2 (0.7–2.0) 1.1 (0.7–1.9)1.0 (0.6–1.7)
1.2 (1.1–1.2)†1.2 (1.1–1.2)† 1.2 (1.1–1.2)†1.1 (1.1–1.2)†
* Depression defined as new incidence of Center for Epidemiologic Studies Depression Scale (CES-D) score at or above 23 compared to the previous
annual interview. OR ? odds ratio; 95% CI ? 95% confidence interval; MI ? myocardial infarction; SLE ? systemic lupus erythematosus; SLAQ ?
Systemic Lupus Activity Questionnaire.
† Significant at P ? 0.05.
Predictors of Depression in SLE545
symptoms. In this model, both persons between the ages of
20 and 39 years (OR 2.1, 95% CI 1.2–3.5) and ages 40–59
years (OR 1.7, 95% CI 1.1–2.6) were more likely to develop
depression, as were persons with some college education
(OR 2.0, 95% CI 1.2–3.2), Hispanic/Latino ethnicity (OR
1.8, 95% CI 1.2–2.8), and increased time 1 depressive
symptom severity (OR 1.2, 95% CI 1.1–1.2). Of the cardio-
vascular characteristics, only the presence of diabetes mel-
litus emerged as being significantly related to the onset of
depression (OR 1.8, 95% CI 1.1–2.7).
The final model incorporated SLE-specific characteris-
tics (model 3) in addition to demographics, time 1 depres-
sive symptoms, and traditional cardiovascular risk and
disease-related factors. In this model, younger age (ages
20–39 years: OR 2.4, 95% CI 1.4–4.2; ages 41–60 years:
OR 1.7, 95% CI 1.1–2.7), some college education (OR 1.8,
95% CI 1.1–3.0), time 1 depression symptom severity (OR
1.1, 95% CI 1.1–1.2), the presence of diabetes mellitus (OR
1.7, 95% CI 1.1–2.7), and baseline assessment of SLE dis-
ease activity (SLAQ per 5 points: OR 1.2, 95% CI 1.1–1.4)
were associated with new-onset depression.
Multivariate analyses of the final model were repeated
with a modified SLAQ, excluding overlapping symptoms
with depression (e.g., depressed mood, fatigue, and forget-
fulness). The results of this model were nearly identical to
the original final model. Significant predictors included
younger age (ages 20–39 years: OR 2.5, 95% CI 1.4–4.3;
ages 40–60 years: OR 1.7, 95% CI 1.1–2.7), some college
educational attainment (OR 1.8, 95% CI 1.1–2.9), Hispanic
ethnicity (OR 1.8, 95% CI 1.2–2.8), baseline depression
symptom severity (OR 1.1, 95% CI 1.1–1.2), the presence
of diabetes mellitus (OR 1.7, 95% CI 1.1–2.6), and the
modified SLAQ (OR 1.4, 95% CI 1.2–1.6). Therefore, to
maintain the psychometric integrity of the SLAQ measure,
the original measure was retained in the model.
In this study, we sought to determine longitudinal predic-
tors of depression in a large cohort of persons with SLE,
with a particular focus on the role of cardiovascular risk
factors and SLE-related disease factors. In multivariate
analyses, our hypotheses were partially supported. We
found that in addition to sociodemographic factors, the
presence of diabetes mellitus and SLE-related disease ac-
tivity were the strongest predictors of the development of
depression in this cohort. Other traditional cardiovascular
risk factors were not significant predictors of the develop-
ment of depression.
The majority of the work evaluating the cardiovascular
disease/depression connection has described the pathway
from depression to increased risk of developing or wors-
ening cardiovascular disease (55). Although the previous
study investigating this link by Greco and colleagues was
cross-sectional, the authors hypothesize that depression
contributes to subclinical markers of atherosclerosis in
patients with SLE (23). Among older adults with substan-
tive accumulation of cardiovascular risk and disease, the
reverse pathway has also been explored, that of depression
precipitated by cardiovascular and cerebrovascular dis-
ease (26). Given the fact that patients with SLE accumulate
substantial cardiovascular burden at a relatively young
age, we hypothesized that this pathway may be bidirec-
tional in SLE and sought to explore this reverse pathway
by evaluating traditional and disease-specific characteris-
tics as risk factors for the longitudinal development of
incident depression over the course of 12 months. In our
multivariate analyses, we observed that the presence of
diabetes mellitus was the only traditional (i.e., Framing-
ham-type) factor associated with the development of de-
Although the presence of diabetes mellitus was not a
common comorbidity in our cohort of SLE patients, this
relationship has also been observed in other populations
(56), and suggests that SLE patients with diabetes mellitus
may be a particularly vulnerable group at risk for the
development of depression. Diabetes mellitus is also a
serious, often difficult to manage chronic condition, and
the burden of these 2 conditions may place an individual
at an increased risk for depression. Additionally, the con-
stellation of metabolic and cardiovascular risk factors
characteristic of diabetes mellitus may contribute to vas-
cular depression, whereas individual risk factors did not
emerge as significant risk factors for depression in this
study. Future studies evaluating specific aspects of diabe-
tes mellitus and clinical cardiovascular risk indices and
profiles are warranted to better understand the role of
these factors in precipitating depression.
Disease activity emerged as the SLE-specific character-
istic most robustly associated with incident depression.
Although few longitudinal studies have been conducted
investigating depression, our results are similar to other
findings suggesting that depression scores appear to par-
allel disease activity over time (22,57). It is possible that
measures of SLE disease activity may reflect increased
systemic inflammation contributing to the development of
subclinical cardiovascular and cerebrovascular disease
that may in turn precipitate the development of depression
akin to the vascular depression hypothesis. Alternatively,
there may exist a direct pathway between inflammation in
the form of increased cytokine production and the devel-
opment of depression (58). Finally, increased disease ac-
tivity may be associated with a range of other downstream
effects (e.g., increased disability, decreased function) that
may confer an additional risk for depression.
Lower education, specifically participants who did not
attain a college degree, was associated with the onset of
depression in this cohort of patients with SLE, supporting
earlier findings in the general population citing a poten-
tially protective effect of increased education (59). In this
study, the lowest level of educational attainment (i.e., high
school or less) was not statistically significant in the mul-
tivariate analyses, but was significant in the bivariate ana-
lyses. We suspect that this lack of significance in the
multivariate analyses is due to decreased power, given our
relatively small sample size for this lowest level of educa-
tion. Increased education has been posited to be associated
with social maturation and improved coping skills as well
as increased social and occupational opportunities (59).
Additionally, income and education are often used inter-
changeably as a marker of socioeconomic status. In this
546Julian et al
study, poverty was not associated with incident depres-
sion unlike our previous studies evaluating prevalent de-
pression (60), suggesting that education and income con-
stitute social determinants exerting unique effects on the
development of depression.
Younger age was a risk factor for depression in this
study, a finding that has been observed in other medical
populations (61). This observation may also be a reflection
of increased disease activity earlier in the course of the
disease contributing to depression through one of the path-
ways described above. However, in the context of the
vascular depression hypothesis, one would expect that
older adults with SLE may have an increased cardiovas-
cular/cerebrovascular burden as a result of living with SLE
for many years and may have increased rates of depression
as they age, which we did not find in this study. This
finding may also be attributed to a reporting bias, specifi-
cally decreased reporting of depressive symptoms among
older adults (62). Additionally, this may be a survivor
effect in that the older adults in our sample may be a
generally healthier subset of older adults with SLE.
Participants who identified their race/ethnicity as His-
panic/Latino were more likely to develop depression as
compared to whites. Other studies have found increased
depression symptom severity in Hispanics (63), and some
observed predictors of depression include greater expo-
sure to stressful life events and in some cases limited
social support (64). It is well known that depression in
Hispanic/Latino patients may be less likely to be detected
by providers, and depression is undertreated in this group
(65), as such leaving this group a potentially vulnerable
subgroup with respect to depression and poor outcomes.
Finally, although the effect is modest, time 1 depressive
symptom severity was a significant risk factor for incident
depression. This finding is not surprising, and highlights
the importance of monitoring patients with minor or sub-
threshold depression in the clinic, as this is a particularly
vulnerable group for the development of more severe de-
pressive disorders (66).
This study is not without limitations. First, we sought to
determine predictors of the development of “depression,”
as defined in this study using cases that cross a threshold
of the CES-D, a measure of depression symptom severity,
and not depressive disorder diagnostic status. Future stud-
ies employing a determination of diagnoses of major de-
pressive disorder are warranted. Related to this issue is the
fact that the incidence of depression was 12% per year,
perhaps limiting our power to detect other significant ef-
fects. Future studies prospectively evaluating the develop-
ment of depression in a large sample of patients with lupus
remain warranted in order to best understand the social
and biologic predictors. Second, interviews of health sta-
tus and depression were conducted annually and like SLE,
depression is a relapsing condition and incident or recur-
rent events within the one-year lag period were not mea-
sured. Third, with the exception of SLE diagnostic status,
the data derived from this cohort are largely self-report.
Although self-reported diagnoses of a number of health
and treatment-related factors have been validated and
deemed reliable in epidemiologic studies (e.g., hyperten-
sion) (67), it is possible that our patients are unaware of
their health status across all traditional and SLE-specific
risk factors. In addition, specific biologic markers (e.g.,
inflammation, presence of antiphospholipid antibodies)
are unavailable for analyses. Perhaps with these biologic
data, we would find more robust associations among a
range of cardiovascular risk factors and depression. Re-
lated to this limitation, the SLAQ as our measure of dis-
ease activity was the most potent predictor of depression,
and although we know that a 5-point increase in SLAQ
score is clinically meaningful, there are not validated cut
points for the SLAQ to characterize disease severity or
specific manifestations (53). Finally, psychosocial and
functional predictors of depression were not evaluated in
this study. It is quite possible that our markers of health
status (e.g., increased disease activity) are associated with
a host of psychosocial and functional sequelae (e.g., in-
creased disability, decreased activity level) that would
confer additional effects on the development of depres-
sion. Our group and others have found increases in func-
tional limitations as important predictors of depression in
rheumatic disease and other chronic conditions (68–72).
Future studies employing a blend of health status and
psychosocial risk factors for depression are necessary to
best elucidate etiologic factors associated with depres-
sion in SLE. Despite these limitations, to our knowledge,
this is the first study to evaluate longitudinally the de-
velopment of depressive symptoms in a large cohort of
patients with SLE. Additionally, this study is hypothesis
generating, in that few studies have focused on the rela-
tionship among cardiovascular disease and risk, a major
cause of morbidity and mortality in SLE, and the develop-
ment of depression.
In conclusion, we found that in addition to younger age
and less education, diabetes mellitus was the only tradi-
tional cardiovascular risk factor associated with the devel-
opment of depression in controlled analyses. SLE-related
disease activity was also an important disease-specific risk
factor for the development of depression. This study
points to potential preventative and interventional ap-
proaches, including the targeting of modifiable risk factors,
that could result in improved depression outcomes in
addition to improved overall health outcomes. Depression
in the context of SLE, like many chronic conditions, is a
substantial risk factor for a host of adverse personal out-
comes for patients, including decreased treatment adher-
ence (73) and increased disability (57,74). In addition to
the personal costs of depression in SLE, mental health
status has emerged as one of the most robust predictors of
health care costs among patients with SLE (75). A number
of effective treatments for depression are available and
identifying patients at risk for significant depressive dis-
orders could substantially improve the quality of life for
patients with SLE.
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors ap-
proved 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, Tonner, Katz.
Predictors of Depression in SLE547
Acquisition of data. Julian, Tonner, Yelin, Trupin, Criswell, Katz.
Analysis and interpretation of data. Julian, Tonner, Yazdany,
1. Ward MM, Lotstein DS, Bush TM, Lambert RE, van Vollen-
hoven R, Neuwelt CM. Psychosocial correlates of morbidity in
women with systemic lupus erythematosus. J Rheumatol
2. Omdal R, Waterloo K, Koldingsnes W, Husby G, Mellgren SI.
Fatigue in patients with systemic lupus erythematosus: the
psychosocial aspects. J Rheumatol 2003;30:283–7.
3. Wekking EM. Psychiatric symptoms in systemic lupus
erythematosus: an update. Psychosom Med 1993;55:219–28.
4. Iverson GL. Psychopathology associated with systemic lupus
erythematosus: a methodological review. Semin Arthritis
5. Shapiro H. Psychopathology in the patient with lupus. In:
Wallace DJ, Hahn BH, editors. Dubois’ lupus erythematosus.
6th ed. Philadelphia: Lippincott, Williams, & Wilkins; 1997.
6. Hay EM, Black D, Huddy A, Creed F, Tomenson B, Bernstein
RM, et al. Psychiatric disorder and cognitive impairment in
systemic lupus erythematosus. Arthritis Rheum 1992;35:
7. Hay EM, Huddy A, Black D, Mbaya P, Tomenson B, Bernstein
RM, et al. A prospective study of psychiatric disorder and
cognitive function in systemic lupus erythematosus. Ann
Rheum Dis 1994;53:298–303.
8. Kozora E, Thompson LL, West SG, Kotzin BL. Analysis of
cognitive and psychological deficits in systemic lupus ery-
thematosus patients without overt central nervous system
disease. Arthritis Rheum 1996;39:2035–45.
9. Brey RL, Holliday SL, Saklad AR, Navarrete MG, Hermosillo-
Romo D, Stallworth CL, et al. Neuropsychiatric syndromes in
lupus: prevalence using standardized definitions. Neurology
10. Bachen LA, Chesney MA, Criswell LA. Prevalence of mood
and anxiety disorders in women with systemic lupus ery-
thematosus. Arthritis Rheum 2009;61:822–9.
11. Nery FG, Borba EF, Viana VS, Hatch JP, Soares JC, Bonfa E,
et al. Prevalence of depressive and anxiety disorders in sys-
temic lupus erythematosus and their association with anti-
ribosomal P antibodies. Prog Neuropsychopharmacol Biol
12. ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomen-
clature. The American College of Rheumatology nomencla-
ture and case definitions for neuropsychiatric lupus syn-
dromes. Arthritis Rheum 1999;42:599–608.
13. Hanly JG. ACR classification criteria for systemic lupus
erythematosus: limitations and revisions to neuropsychiatric
variables. Lupus 2004;13:861–4.
14. Ainiala H, Loukkola J, Peltola J, Korpela M, Hietaharju A. The
prevalence of neuropsychiatric syndromes in systemic lupus
erythematosus. Neurology 2001;57:496–500.
15. Nived O, Sturfelt G, Liang MH, De Pablo P. The ACR nomen-
clature for CNS lupus revisited. Lupus 2003;12:872–6.
16. Hanly JG, Su L, Farewell V, McCurdy G, Fougere L, Thomp-
son K. Prospective study of neuropsychiatric events in sys-
temic lupus erythematosus. J Rheumatol 2009;36:1449–59.
17. Hanly JG, Urowitz MB, Su L, Bae SC, Gordon C, Wallace DJ,
et al, for the Systemic Lupus International Collaborating Clin-
ics (SLICC). Prospective analysis of neuropsychiatric events
in an international disease inception cohort of patients with
systemic lupus erythematosus. Ann Rheum Dis 2010;69:529–
18. Abdel-Nasser AM, Ghaleb RM, Mahmoud JA, Khairy W,
Mahmoud RM. Association of anti-ribosomal P protein anti-
bodies with neuropsychiatric and other manifestations of sys-
temic lupus erythematosus. Clin Rheumatol 2008;27:1377–
19. Lapteva L, Nowak M, Yarboro CH, Takada K, Roebuck-
Spencer T, Weickert T, et al. Anti-N-methyl-D-aspartate re-
ceptor antibodies, cognitive dysfunction, and depression in
systemic lupus erythematosus. Arthritis Rheum 2006;54:
20. Morgan M, Downs K, Chesterman CN, Biggs JC. Clinical ana-
lysis of 125 patients with the lupus anticoagulant. Aust
N Z J Med 1993;23:151–6.
21. Nery FG, Borba EF, Hatch JP, Soares JC, Bonfa E, Neto FL.
Major depressive disorder and disease activity in systemic
lupus erythematosus. Compr Psychiatry 2007;48:14–9.
22. Ward MM, Marx AS, Barry NN. Psychological distress and
changes in the activity of systemic lupus erythematosus.
Rheumatology (Oxford) 2002;41:184–8.
23. Greco CM, Kao AH, Sattar A, Danchenko N, Maksimowicz-
McKinnon KM, Edmundowicz D, et al. Association between
depression and coronary artery calcification in women with
systemic lupus erythematosus. Rheumatology (Oxford) 2009;
24. Lisitsyna TA, Vel’tishchev D, Seravina OF, Kovalevskaia OB,
Marchenko AS, Novikova DS, et al. Prevalence of mental
disorders in SLE patients: correlations with the disease activ-
ity and comorbid chronic conditions. Ter Arkh 2009;81:10–6.
25. Krishnan KR, McDonald WM. Arteriosclerotic depression.
Med Hypotheses 1995;44:111–5.
26. Alexopoulos GS. The vascular depression hypothesis: 10
years later. Biol Psychiatry 2006;60:1304–5.
27. Krishnan KR. Towards a scientific taxonomy of depression.
Dialogues Clin Neurosci 2008;10:301–8.
28. Roman GC. Vascular depression: an archetypal neuropsychi-
atric disorder. Biol Psychiatry 2006;60:1306–8.
29. Salmon JE, Roman MJ. Subclinical atherosclerosis in rheuma-
toid arthritis and systemic lupus erythematosus. Am J Med
30. Roman MJ, Shanker BA, Davis A, Lockshin MD, Sammaritano
L, Simantov R, et al. Prevalence and correlates of accelerated
atherosclerosis in systemic lupus erythematosus. N Engl
J Med 2003;349:2399–406.
31. Kao AH, Sabatine JM, Manzi S. Update on vascular disease in
systemic lupus erythematosus. Curr Opin Rheumatol 2003;
32. Kaell AT, Shetty M, Lee BC, Lockshin MD. The diversity of
neurologic events in systemic lupus erythematosus: prospec-
tive clinical and computed tomographic classification of 82
events in 71 patients. Arch Neurol 1986;43:273–6.
33. Sibley JT, Olszynski WP, Decoteau WE, Sundaram MB. The
incidence and prognosis of central nervous system disease in
systemic lupus erythematosus. J Rheumatol 1992;19:47–52.
34. Bessant R, Duncan R, Ambler G, Swanton J, Isenberg DA,
Gordon C, et al. Prevalence of conventional and lupus-
specific risk factors for cardiovascular disease in patients with
systemic lupus erythematosus: a case–control study. Arthritis
35. Asanuma Y, Oeser A, Shintani AK, Turner E, Olsen N, Fazio
S, et al. Premature coronary-artery atherosclerosis in systemic
lupus erythematosus. N Engl J Med 2003;349:2407–15.
36. Frostegard J. SLE, atherosclerosis and cardiovascular disease.
J Intern Med 2005;257:485–95.
37. Esdaile JM, Abrahamowicz M, Grodzicky T, Li Y, Panaritis C,
du Berger R, et al. Traditional Framingham risk factors fail to
fully account for accelerated atherosclerosis in systemic
lupus erythematosus. Arthritis Rheum 2001;44:2331–7.
38. Davis JM 3rd, Maradit Kremers H, Crowson CS, Nicola PJ,
Ballman KV, Therneau TM, et al. Glucocorticoids and cardio-
vascular events in rheumatoid arthritis: a population-based
cohort study. Arthritis Rheum 2007;56:820–30.
39. Maxwell SR, Moots RJ, Kendall MJ. Corticosteroids: do they
damage the cardiovascular system? Postgrad Med J 1994;70:
40. Abou-Raya A, Abou-Raya S. Inflammation: a pivotal link be-
tween autoimmune diseases and atherosclerosis. Autoimmun
41. Bertoli AM, Vila LM, Reveille JD, Alarcon GS. Systemic lupus
erythematosus in a multiethnic US cohort (LUMINA): LXI.
548 Julian et al
Value of C-reactive protein as a marker of disease activity and Download full-text
damage. J Rheumatol 2008;35:2355–8.
42. Yip GW, Shang Q, Tam LS, Zhang Q, Li EK, Fung JW, et al.
Disease chronicity and activity predict subclinical left ven-
tricular systolic dysfunction in patients with systemic lupus
erythematosus. Heart 2009;95:980–7.
43. Chaiamnuay S, Bertoli AM, Roseman JM, McGwin G, Apte M,
Duran S, et al. African-American and Hispanic ethnicities,
renal involvement and obesity predispose to hypertension in
systemic lupus erythematosus: results from LUMINA, a mul-
tiethnic cohort (LUMINAXLV). Ann Rheum Dis 2007;66:618–
44. Toloza SM, Uribe AG, McGwin G Jr, Alarcon GS, Fessler BJ,
Bastian HM, et al. Systemic lupus erythematosus in a multi-
ethnic US cohort (LUMINA): XXIII. Baseline predictors of
vascular events. Arthritis Rheum 2004;50:3947–57.
45. Calvo-Alen J, Toloza SM, Fernandez M, Bastian HM, Fessler
BJ, Roseman JM, et al. Systemic lupus erythematosus in a
multiethnic US cohort (LUMINA). XXV. Smoking, older age,
disease activity, lupus anticoagulant, and glucocorticoid dose
as risk factors for the occurrence of venous thrombosis in
lupus patients. Arthritis Rheum 2005;52:2060–8.
46. Hochberg MC, for the Diagnostic and Therapeutic Criteria
Committee of the American College of Rheumatology. Updat-
ing the American College of Rheumatology revised criteria for
the classification of systemic lupus erythematosus [letter].
Arthritis Rheum 1997;40:1725.
47. Yelin E, Trupin L, Katz P, Criswell L, Yazdany J, Gillis J, et al.
Work dynamics among persons with systemic lupus erythem-
atosus. Arthritis Rheum 2007;57:56–63.
48. Radloff LS. The CES-D Scale: a self-report depression measure
for research in the general population. Appl Psychol Meas
49. Pandya R, Metz L, Patten SB. Predictive value of the CES-D in
detecting depression among candidates for disease-modifying
multiple sclerosis treatment. Psychosomatics 2005;46:131–4.
50. Haringsma R, Engels GI, Beekman AT, Spinhoven P. The
criterion validity of the Center for Epidemiological Studies
Depression Scale (CES-D) in a sample of self-referred elders
with depressive symptomatology. Int J Geriatr Psychiatry
51. Barrett J, Oxman T, Gerber P. Prevalence of depression and its
correlates in a general medical practice. J Affect Disord 1987;
52. Karlson EW, Daltroy LH, Rivest C, Ramsey-Goldman R,
Wright EA, Partridge AJ, et al. Validation of a Systemic Lupus
Activity Questionnaire (SLAQ) for population studies. Lupus
53. Yazdany J, Yelin EH, Panopalis P, Trupin L, Julian L, Katz PP.
Validation of the systemic lupus erythematosus activity ques-
tionnaire in a large observational cohort. Arthritis Rheum
54. Hardin JW, Hilbe JM. Generalized estimating equations. Boca
Raton (FL): Chapman & Hall/CRC; 2002.
55. Van der Kooy K, van Hout H, Marwijk H, Marten H, Stehou-
wer C, Beekman A. Depression and the risk for cardiovascular
diseases: systematic review and meta analysis. Int J Geriatr
56. Katon W, Russo J, Lin EH, Heckbert SR, Ciechanowski P,
Ludman EJ, et al. Depression and diabetes: factors associated
with major depression at five-year follow-up. Psychosomatics
57. Nery FG, Borba EF, Hatch JP, Soares JC, Bonfa E, Neto FL.
Major depressive disorder and disease activity in systemic
lupus erythematosus. Compr Psychiatry 2007;48:14–9.
58. Irwin MR, Miller AH. Depressive disorders and immunity: 20
years of progress and discovery. Brain Behav Immun 2007;21:
59. Ladin K. Risk of late-life depression across 10 European
Union countries: deconstructing the education effect. J Aging
60. Trupin L, Tonner MC, Yazdany J, Julian LJ, Criswell LA, Katz
PP, et al. The role of neighborhood and individual socio-
economic status in outcomes of systemic lupus erythemato-
sus. J Rheumatol 2008;35:1782–8.
61. Strik JJ, Lousberg R, Cheriex EC, Honig A. One year cumula-
tive incidence of depression following myocardial infarction
and impact on cardiac outcome. J Psychosom Res 2004;56:
62. Lyness JM, Cox C, Curry J, Conwell Y, King DA, Caine ED.
Older age and the underreporting of depressive symptoms.
J Am Geriatr Soc 1995;43:216–21.
63. Bromberger JT, Schott LL, Kravitz HM, Sowers M, Avis NE,
Gold EB, et al. Longitudinal change in reproductive hormones
and depressive symptoms across the menopausal transition:
results from the Study of Women’s Health Across the Nation
(SWAN). Arch Gen Psychiatry 2010;67:598–607.
64. Boutin-Foster C, Ogedegbe G, Peterson J, Briggs WM, Alle-
grante JP, Charlson ME. Psychosocial mediators of the rela-
tionship between race/ethnicity and depressive symptoms in
Latino and white patients with coronary artery disease. J Natl
Med Assoc 2008;100:849–55.
65. Simpson S, Krishnan L, Kunik M, Ruiz P. Racial disparities in
diagnosis and treatment of depression: a literature review.
Psychiatr Q 2007;78:3–14.
66. Fogel J, Eaton WW, Ford DE. Minor depression as a predictor
of the first onset of major depressive disorder over a 15-year
follow-up. Acta Psychiatr Scand 2006;113:36–43.
67. Vargas CM, Burt VL, Gillum RF, Pamuk ER. Validity of self-
reported hypertension in the National Health and Nutrition
Examination Survey III, 1988-1991. Prev Med 1997;26:678–
68. Gitlin LN, Hauck WW, Dennis MP, Schulz R. Depressive
symptoms in older African-American and white adults with
functional difficulties: the role of control strategies. J Am
Geriatr Soc 2007;55:1023–30.
69. Katz PP, Julian LJ, Omachi TA, Gregorich SE, Eisner MD,
Yelin EH, et al. The impact of disability on depression among
individuals with COPD. Chest 2009;137:838–45.
70. Margaretten M, Yelin E, Imboden J, Graf J, Barton J, Katz P,
et al. Predictors of depression in a multiethnic cohort of
patients with rheumatoid arthritis. Arthritis Rheum 2009;61:
71. Katz PP, Yelin EH. Activity loss and the onset of depressive
symptoms: do some activities matter more than others? Arthritis
72. Katz PP, Yelin EH. The development of depressive symptoms
among women with rheumatoid arthritis: the role of function.
Arthritis Rheum 1995;38:49–56.
73. Julian LJ, Yelin E, Yazdany J, Panopalis P, Trupin L, Criswell
LA, et al. Depression, medication adherence, and service uti-
lization in systemic lupus erythematosus. Arthritis Rheum
74. Baker K, Pope J, Fortin P, Silverman E, Peschken C, for the
1000 Faces of Lupus Investigators and CaNIOS (Canadian
Network for Improved Outcomes in SLE). Work disability in
systemic lupus erythematosus is prevalent and associated
with socio-demographic and disease related factors. Lupus
75. Panopalis P, Yazdany J, Gillis JZ, Julian L, Trupin L, Hersh
AO, et al. Health care costs and costs associated with changes
in work productivity among persons with systemic lupus
erythematosus. Arthritis Rheum 2008;59:1788–95.
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