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com

Extended report

Prospective analysis of neuropsychiatric events in

an international disease inception cohort of patients
with systemic lupus erythematosus
J G Hanly,1 M B Urowitz,2 L Su,3 S C Bae,4 C Gordon,5 D J Wallace,6 A Clarke,7
S Bernatsky,8 D Isenberg,9 A Rahman,9 G S Alarcón,10 D D Gladman,2 P R Fortin,2
J Sanchez-Guerrero,11 J Romero-Diaz,11 J T Merrill,12 E Ginzler,13 I N Bruce,14
K Steinsson,15 M Khamashta,16 M Petri,17 S Manzi,18 M A Dooley,19 R Ramsey-Goldman,20
R Van Vollenhoven,21 O Nived,22 G Sturfelt,22 C Aranow,23 K Kalunian,24 M Ramos-Casals,25
A Zoma,26 J Douglas,1 K Thompson,1 V Farewell3 for the Systemic Lupus International
Collaborating Clinics (SLICC)

▶ Additional data are ABSTRACT An international, multicentre, prospective,

published online only at http:// Objectives To determine the frequency, accrual, inception cohort study of NP events in patients
ard.bmj.com/content/vol69/ attribution and outcome of neuropsychiatric (NP) with SLE was undertaken using uniform defini-
issue3
events and impact on quality of life over 3 years in a tions and decision rules for determination of
For numbered affiliations see large inception cohort of patients with systemic lupus attribution. We previously reported on NP events
end of article erythematosus (SLE). at enrolment,6 including short-term outcome over
Methods The study was conducted by the Systemic a mean of 3.7 months. In this study, we report
Correspondence to
Lupus International Collaborating Clinics. Patients were the clinical characteristics, outcome and impact
Dr John G Hanly, QEII Health
Sciences Centre and Dalhousie enrolled within 15 months of SLE diagnosis. NP events were on health-related quality of life (HRQoL) in an
University, 1341 Summer identified using the American College of Rheumatology case expanded cohort of patients evaluated over 3
Street, Halifax, NS B3H 4K4, definitions, and decision rules were derived to determine the years and up to four annual assessments with a
Canada; john.hanly@cdha. mean follow-up of 23 months.
proportion of NP disease attributable to SLE. The outcome
nshealth.ca
of NP events was recorded and patient-perceived impact
Accepted 31 March 2009 determined by the SF-36.
PATIENTS AND METHODS
Published Online First Results 1206 patients (89.6% female) with a mean
Research network
8 April 2009 (±SD) age of 34.5±13.2 years were included in the
The study was performed by the Systemic Lupus
study. The mean disease duration at enrolment was
International Collaborating Clinics (SLICC)7
5.4±4.2 months. Over a mean follow-up of 1.9±1.2
between October 1999 and February 2008 and was
years, 486/1206 (40.3%) patients had ≥1 NP events,
approved by the Capital Health Research Ethics
which were attributed to SLE in 13.0–23.6% of patients
Board, Halifax, Nova Scotia, Canada and by the
using two a priori decision rules. The frequency of
institutional research ethics boards of participating
individual NP events varied from 47.1% (headache) to 0%
centres.
(myasthenia gravis). The outcome was significantly better
for those NP events attributed to SLE, especially if they
occurred within 1.5 years of the diagnosis of SLE. Patients Patients
with NP events, regardless of attribution, had significantly Patients fulfilled the American College of
lower summary scores for both mental and physical Rheumatology (ACR) classification criteria for
health over the study. SLE8 and provided written informed consent. The
Conclusions NP events in patients with SLE are of date of diagnosis was taken as the point at which
variable frequency, most commonly present early in the four or more ACR criteria were first recognised,
disease course and adversely impact patients’ quality of and enrolment occurred up to 15 months after the
life over time. Events attributed to non-SLE causes are diagnosis. Patients were reviewed at enrolment
more common than those due to SLE, although the latter and annually (±6 months) thereafter when new
have a more favourable outcome. NP events since the previous visit and the status of
old events were recorded. Other data included age,
gender, ethnicity, education, medication use, SLE
INTRODUCTION Disease Activity Index (SLEDAI)9 and SLICC/ACR
The frequency of neuropsychiatric (NP) disease in Damage Index (SDI).10 HRQoL was measured by
systemic lupus erythematosus (SLE) varies between the SF-36.11 Laboratory data included a complete
37% and 95%.1–5 Differences in the definition and blood count, serum creatinine, urine analysis, anti-
ascertainment of NP manifestations, lack of consis- DNA, C3 and C4.
tency in the attribution of NP events and inclusion
of subtle NP disease of uncertain clinical signifi- Neuropsychiatric events
cance contribute to this variability. The fluctuating All NP events were characterised using the ACR
course of many NP manifestations emphasises the case definitions and were diagnosed by clinical eval-
need to evaluate their impact over time. uation supported with appropriate investigations

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Extended report

according to the ACR glossary12 (see online supplementary Table 1 Demographic and clinical manifestations of patients with
file #1). The exception was cognitive impairment, for which the systemic lupus erythematosus (SLE) at enrolment visit
diagnosis was made by formal neuropsychological testing in
Number of patients 1206
only 9/43 (21%) cases.
Gender (n (%))
Female 1080 (89.6)
Outcome of NP events Male 126 (10.4)
A doctor-generated seven-point Likert scale compared the change Age (years) (mean ± SD) at enrolment 34.5±13.2
in NP status between the onset of the event and time of study Ethnicity (%)
assessment (1=patient demise, 2=much worse, 3=worse, 4=no Caucasian 47.4
change, 5=improved, 6=much improved, 7=resolved). The time Hispanic 16.5
Asian 16.5
to resolution was the interval between the onset of the event
Black 15.6
and the date of resolution; if the NP event had not resolved,
Other 3.9
the time was censored to onset of the event and the date of the Region (%)
final assessment. Analyses of both time to resolution and Likert Canada 22.2
outcome scores were undertaken. A patient-generated mental USA, Mexico 41.4
(MCS) and physical (PCS) component summary score of the Europe 25.1
SF-3611 determined the impact of NP events on HRQoL. Asia 11.3
Single/married/other (%) 46.6/40.8/12.6
Post-secondary education (%) 62.1
Statistical analysis
Disease duration (months) (mean±SD) 5.4 ± 4.2
NP events were attributed to SLE or non-SLE causes (see online Number of ACR criteria (mean±SD) 4.5 ±1.01
supplementary file #1) and categorised into central/peripheral Cumulative ACR manifestations (n (%))
and diffuse/focal nervous system manifestations as described6 12 Malar rash 501 (41.5)
(see supplementary file #2). SLICC centres were grouped into Discoid rash 174 (14.4)
geographical locations (Canada, USA/Mexico, Europe, Asia). Photosensitivity 434 (36.0)
For some analyses patients were categorised at each assessment Oral/nasopharyngeal ulcers 539 (44.7)
as NP positive with (A) diffuse/central events only; (B) focal/ Serositis 336 (27.9)
peripheral events only; (C) both events and (D) an NP negative Arthritis 886 (73.5)
Renal disorder 346 (28.7)
group.
Neurological disorder 71 (5.9)
χ2 and t tests examined differences in demographics and NP
Haematological disorder 742 (61.5)
status at enrolment between patients with missing data and Immunological disorder 923 (76.5)
patients who completed the study. Explanatory variables for Antinuclear antibody 1158 (96.0)
time-to-case resolution for NP events were examined using SLEDAI score (mean±SD) 5.4 ± 5.5
Cox regression (adjusting for correlation of events in the same SLICC/ACR score (mean±SD) 0.3 ± 0.8
patient). Medications (%)
Likert outcome scores of NP events were analysed using Corticosteroids 835 (69.2)
multilevel ordinal logistic regression, with odds ratios linked to Antimalarial agents 744 (61.7)
the probability of higher, more favourable, scores, and account- Immunosuppressant agents 471 (39.1)
Aspirin 170 (14.1)
ing for correlation of multiple scores over time for the same
Antidepressants 105 (8.7)
event and multiple events for the same patient. SF-36 analyses
Anticonvulsants 48 (4.0)
used linear regression and generalised estimating equations with Warfarin 59 (4.9)
a first-order autoregressive correlation structure to allow for cor- Antipsychotics 7 (0.6)
relation between multiple SF-36 measurements for the same
ACR, American College of Rheumatology; SLEDAI, SLE Disease Activity Index; SLICC,
patient. Systemic Lupus International Collaborating Clinics.

RESULTS
Patients
A total of 1206 patients were recruited in 24 centres. Patients Frequency and attribution of NP events
were predominantly female (89.6%) and Caucasian with a Four hundred and eighty-six of 1206 (40.3%) patients had at
mean±SD age of 34.5±13.2 years (table 1). least one NP event during the study; 210 (17.4%) had two or
The mean disease duration was 5.4±4.2 months in an more events. The 486 patients had 843 events encompassing
unselected patient population with moderate disease activity. 18/19 NP syndromes (table 2).
The mean follow-up for NP events (the onset of NP events to The most common events were headache (migraine (49%),
the last assessment) was 1.9±1.2 years. No follow-up was avail- tension (38%), intractable 9%, cluster (3%), pseudotumour
able in 191/1206 (15.8%) patients and the assessment for the cerebri (1%)), mood disorders, seizures, cognitive dysfunction,
last expected date plus 6 months was unavailable in 353/1206 anxiety disorder, cerebrovascular disease, acute confusional
(29.3%). These patients were more likely to be younger (p<0.008), state, polyneuropathy and mononeuropathy. The remaining 10
Hispanic or Black (p<0.0001), had less education (p<0.006) and NP syndromes had a prevalence of <2%; myasthenia gravis did
higher SLEDAI scores (6.1±6.3 vs 5.2±5.2; p<0.023). They were not occur in any patient.
also less likely to have NP disease, attributed to SLE or non- NP events attributed to SLE varied from 17.7% (model A) to
SLE causes, at the enrolment assessment (p<0.023). There were 30.6% (model B) (table 2). Of the 843 NP events, 785 (93.1%)
18/1206 (1.5%) deaths and in 4/18 (22.2%) cases the primary affected the central nervous system and 58 (6.9%) involved
cause was attributed to NP events (intracranial haemorrhage the peripheral nervous system. Diffuse and focal events were
(two), stroke (one), seizures (one)). 666 (79%) and 177 (21%), respectively. The most common NP

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Extended report

Table 2 The number of neuropsychiatric (NP) events by attribution over the period of study
SLE NP events SLE NP events Non-SLE
(model A) (model B) NP events Total NP events
Event types No % No % No % No %
Headache 0 0.00 0 0.0 397 67.9 397 47.1
Mood disorders 18 12.1 47 18.2 92 15.7 139 16.5
Seizures and seizure disorders 39 26.2 54 20.9 9 1.5 63 7.5
Cognitive dysfunction 8 5.4 22 8.5 21 3.6 43 5.1
Anxiety disorder 0 0.0 0 0.0 42 7.2 42 4.9
Cerebrovascular disease 18 12.1 40 15.5 0 0.0 40 4.7
Acute confusional state 11 7.4 17 6.6 5 0.9 22 2.6
Polyneuropathy 8 5.4 10 3.9 10 1.7 20 2.4
Mononeuropathy 10 6.7 18 6.9 0 0.0 18 2.1
Neuropathy, cranial 11 7.4 11 4.3 4 0.7 15 1.8
Psychosis 8 5.4 13 5.0 1 0.2 14 1.7
Myelopathy 5 3.4 10 3.9 0 0.0 10 1.2
Movement disorder 4 2.7 5 1.9 1 0.2 6 0.7
Aseptic meningitis 4 2.7 4 1.6 2 0.3 6 0.7
Demyelinating syndrome 1 0.7 3 1.2 0 0.0 3 0.4
Acute inflammatory 2 1.3 2 0.8 0 0.0 2 0.2
Autonomic disorder 2 1.3 2 0.8 0 0.0 2 0.2
Plexopathy 0 0.0 0 0.0 1 0.2 1 0.1
Myasthenia gravis 0 0.0 0 0.0 0 0.0 0 0.0
Total (%) NP events 149 (17.7) 258 (30.6) 585 (69.4) 843 (100)

events attributed to SLE were seizures, mood disorders, cerebro- particularly at the first two study assessments (figure 3).
vascular disease and acute confusional states. Controlling for the duration of follow-up, multivariate ordinal
regression analysis confirmed a significant positive association
Onset and accrual of NP events between favourable outcome scores and SLE NP events (model
NP events were most common at the enrolment visit and the B) (odds ratio (OR)=1.51, 95% CI 1.05 to 2.21, p=0.028), focal
cumulative incidence of both SLE and non-SLE NP events NP events (OR=1.83, 95% CI 1.28 to 2.64, p=0.001), US/Mexico
increased over time (figure 1). Of patients with follow-up to the (OR=1.32, 95% CI 0.90 to 1.93), European (OR=1.66, 95% CI
final study assessment, 51.2% had at least one NP event. The 1.12 to 2.46) and Asian (OR=2.79, 95% CI 1.41 to 5.50) sites
proportion of patients with NP events attributed to SLE varied (p=0.007), and negative associations with older age at SLE diag-
between 13.0% (model A) and 23.6% (model B). The proportion nosis (OR=0.69, 95% CI 0.59 to 0.81), p<0.001), longer disease
of patients with both SLE and non-SLE attributed NP events was duration at event onset (OR=0.79, 95% CI 0.69 0.90), p=0.001)
7.9% (model A) and 14.2% (model B).

Outcome of NP events
There was no difference in the attribution frequency of new,
recurring or ongoing NP events (figure 2). However, the rate of
resolution of NP events attributed to SLE was higher than events
due to non-SLE causes (model A: 55.0% vs 38.2%, hazard ratio
(HR)=1.62, 95% CI 1.24 to 2.11, p<0.001; model B: 51.9% vs
36.4%, HR=1.53, 95% CI 1.22 to 1.92, p<0.001). There was a
higher resolution of focal versus diffuse NP events (52.5% vs
38.1%, HR=1.55, 95% CI1.21 to 1.98, p<0.001) but no difference
between the resolution of central versus peripheral NP events
(41.4% vs 37.9%, HR=1.23, 95% CI 0.79 to 1.93, p=0.358).
To look for an interaction between disease duration and the
effect of attribution on NP event resolution, disease duration
at the occurrence of events was dichotomised at 1.5 years. For
model A the estimated SLE attribution effect on resolution of
events within 1.5 years of the diagnosis of SLE was larger than
the effect for events occurring ≥1.5 years after the diagnosis Figure 1 The cumulative frequency of patients with neuropsychiatric
(NP) events at enrolment and at subsequent study assessments. The
(HR=1.77 vs 0.89) (interaction coefficient=−0.69, 95% CI −1.52
percentage of patients with NP events is shown at each time point for
to 0.15, p=0.107). For model B, the same analysis led to a hazard all NP events regardless of attribution (all NP), NP events attributed
ratio comparison of: 1.66 vs 0.86 (interaction coefficient=−0.66, to non-systemic lupus erythematosus (SLE) causes (non-SLE NP), NP
95% CI −1.39 to 0.07, p=0.076). events attributed to SLE according to attribution model B (SLE NP (B))
Favourable Likert outcome scores for NP events were more and NP events attributed to SLE according to attribution model A (SLE
common for those attributed to SLE (model A or model B), NP (A)).

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Figure 2 The frequency of neuropsychiatric (NP) events at enrolment and at subsequent study assessments characterised as new, recurring or ongoing
from a previous assessment. At each assessment the status of the NP events into resolved or unresolved is shown. Summary data are shown for NP
events regardless of attribution (all NP events), NP events attributed to systemic lupus erythematosus (SLE) according to attribution model A (SLE NP
(model A)), NP events attributed to SLE according to attribution model B (SLE NP (model B)) and NP events attributed to non-SLE causes (non-SLE NP).

Figure 3 The outcome of neuropsychiatric (NP) events over the duration of the study. Events are clustered into all NP events regardless of
attribution (all NP events), NP events attributed to systemic lupus erythematosus (SLE) according to attribution model A (SLE NP events (model A)),
NP events attributed to SLE according to attribution model B (SLE NP events (model B)) and NP events attributed to non-SLE causes (non-SLE NP
events). Within each panel the outcome of the events is scored as much worse, worse, no change, improved, much improved and resolved at
assessments 1 through 4 compared with the onset of the event.

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and higher SLEDAI scores computed without NP variables Similarly, the group means for the PCS scores were signifi-
(OR=0.95, 95% CI 0.93 to 0.98), p=0.002), all of which were cantly lower in patients with NP events (estimate: −3.3, 95%
included in the models as continuous variables. The interaction CI −4.5 to −2.1, p<0.001) regardless of attribution (figure 4). In
between disease duration at event onset and attribution of an a summary multivariate analysis controlling for ethnicity, age at
NP event was again only marginally significant (p=0.095). SLE diagnosis and disease duration at each visit, other significant
associations with lower PCS scores were with study sites (eg,
NP events and HRQoL US/Mexico vs rest: estimate: −5.3, 95% CI −7.2 to −3.4; global
In a multivariate regression analysis there were significantly p<0.001); female gender (estimate: −2.3, 95% CI −4.3 to −0.3,
lower MCS scores in patients with NP events regardless of attri- p=0.024); lack of college education (estimate: −2.7, 95% CI −4.1
bution than in those without events (estimate: −9.7, 95% CI to −1.3, p<0.001); higher SLEDAI scores (estimate: −0.35, 95%
−12.7 to −6.7; p<0.001) (figure 4). Controlling for gender, age at CI −0.48 to −0.22, p<0.001) and higher SDI scores (eg, SDI >3 vs
SLE diagnosis, disease duration at each visit, a summary multi- ≤3: estimate: −5.2, 95% CI −8.9 to −1.5; global p<0.001) com-
variate analysis also demonstrated associations between lower puted without NP variables.
MCS scores and diffuse NP events (eg, patients with diffuse
vs focal NP events only: estimate=−5.0, 95% CI −9.2 to −0.8; DISCUSSION
global p=0.041); higher SLEDAI scores (estimate: −0.15, 95% CI We have established a large, SLE disease inception cohort for
−0.30 to −0.01, p=0.041) and higher SDI scores, both computed the systematic evaluation of NP events in a long-term prospec-
without NP variables (eg, SDI >3 vs ≤3: estimate=−5.7, 95% CI tive study. A unique feature of the study is inclusion of all NP
−10.4 to −0.9; global p=0.039). events regardless of their aetiology, so that differences in the
outcome and impact of NP events due to SLE and other causes
could be compared. Attribution of NP events was determined
using predefined decision rules which have previously provided
a positive correlation between SLE NP events and pathogenic
autoantibodies.13 Over the study, 40.3% of patients had at
least one NP event and 17.4% had multiple events. However,
patients with NP events attributed to SLE varied from 13.0% to
23.6%, depending upon the stringency of the attribution rules.
Likewise, only 17.7% to 30.6% of all NP events were attributed
to SLE. Finally, many of the 19 syndromes occurred in <2% of
patients, indicating that they are relatively infrequent, at least in
the first 3 years of the disease.
The outcome of NP events in patients with SLE, particularly
those attributed directly to SLE, has been informed by clinical
trials,14–19 retrospective and prospective observational cohorts
and case series,20 21 with inconsistent results. In this study the
most favourable outcomes occurred with NP events attributed
to SLE compared with non-SLE causes and with focal NP com-
pared with diffuse NP events. Furthermore, the outcome was
best in SLE-attributed events when they occurred early in the
disease course, suggesting that the attribution and time of onset
of NP events predict outcome. As for rheumatoid arthritis22 23
this may indicate a therapeutic window of opportunity when
pathogenetic mediators are amenable to immunosuppressive
and anti-inflammatory treatments. This study confirms and
expands the findings of previous cross-sectional studies reporting
that NP events, regardless of attribution, are associated with a
significant reduction in patient self-reported HRQoL.3 24 25 Thus,
in addition to lower group means for MCS and PCS scores of the
SF-36 in patients with NP events compared with those without
NP events at enrolment, the same group differences persist over
the ensuing 3 years. Our results also emphasise the importance
of assessing the impact of all NP manifestations, as studies con-
fined to specific subsets of NP disease such as cognitive dysfunc-
tion have not found a negative effect on HRQoL.26 27
There are potential limitations to our study. First, the fre-
quency of patients with unavailable data (29%) or no follow-up
(15.8%) by the final study assessment is high compared with
some longitudinal lupus cohorts with rates as low as 11%.28 29
Figure 4 Mean mental component summary (MCS) score and
physical component summary (PCS) score of the Short Form-36 (SF-36) However, these cohorts were more homogeneous and followed
over the period of study in patients with no NP events (NP negative), NP up at single centres. In contrast, 29% lost to follow-up over 3.5
events attributed to non-systemic lupus erythematosus (SLE) causes years was reported in a large, multiethnic, multicentre cohort
(non-SLE NP) and NP events attributed to SLE according to attribution with very similar predictors as in our study.30 Second, restrict-
model A or B (SLE NP A or B) at each of the study assessments. (See ing NP syndromes to the 19 ACR case definitions12 might have
supplementary file #3) excluded some NP presentations. However, none of the 1206

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Extended report

patients had an NP event which could not be captured within (distinguished senior research investigator of the Arthritis Society and Arthritis Centre
the ACR definitions. Finally, formal neuropsychological assess- of Excellence); MP (Hopkins Lupus Cohort grant AR 43727, Johns Hopkins University
General Clinical Research Center grant MO1 RR00052); SM(National Institutes of
ments were not performed on all patients and neuroimaging Health research grants R01 AR46588, K24 AR002213 and M01 RR000056); RR-G
studies were only done if clinically indicated. Although addi- (National Institutes of Health research grants M01-RR00048; K24 AR02318; P60 AR
tional abnormalities would probably have been detected by 48098); ON (Swedish Medical Research council grant 13489); GS (Swedish Medical
both techniques, our protocol was intended to reflect clinical Research council grant 13489); VF (MRC(UK) grant U.1052.00.009).
practice and to avoid the inclusion of subtle NP disease with Competing interests None.
limited clinical significance.26 31–36 Ethics approval This study was conducted with the approval of the Capital Health
In summary our findings indicate a high cumulative frequency Research Ethics Board, Halifax, Nova Scotia, Canada and by the institutional research
of NP events and a negative impact on HRQoL, even though the ethics boards of participating centres in accordance with the Declaration of Helsinki’s
majority of NP events are not attributable to SLE. Those events guidelines for research in humans.
attributed to SLE and focal NP events have a better outcome. Provenance and peer review Not commissioned; externally peer reviewed.
Future studies will examine the long-term course and impact of
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49529, Lupus Foundation of Ontario, Ontario Lupus Association, Lupus UK, Lupus refractory systemic lupus erythematosus involving the central nervous system. Ann
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Clinical Research Facility in Birmingham, UK); AC (Fonds de la recherche en santé 20. Karassa FB, Ioannidis JP, Boki KA, et al. Predictors of clinical outcome and radiologic
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Institutes of Health Research Junior Investigator Award; Fonds de la recherche en erythematosus. Am J Med 2000;109:628–34.
santé du Québéc Jeune Chercheure; Canadian Arthritis Network Scholar Award; 21. Jönsen A, Bengtsson AA, Nived O, et al. Outcome of neuropsychiatric systemic
McGill University Health Centre Research Institute); GSA (University of Alabama at lupus erythematosus within a defined Swedish population: increased morbidity but
Birmingham, grant P60AR48095); DDG (Canadian Institutes of Health Research); PRF low mortality. Rheumatology (Oxford) 2002;41:1308–12.

534 Ann Rheum Dis 2010;69:529–535. doi:10.1136/ard.2008.106351

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Ann Rheum Dis 2010;69:529–535. doi:10.1136/ard.2008.106351 535

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Prospective analysis of neuropsychiatric

events in an international disease inception
cohort of patients with systemic lupus
erythematosus
J G Hanly, M B Urowitz, L Su, S C Bae, C Gordon, D J Wallace, A Clarke,
S Bernatsky, D Isenberg, A Rahman, G S Alarcón, D D Gladman, P R
Fortin, J Sanchez-Guerrero, J Romero-Diaz, J T Merrill, E Ginzler, I N
Bruce, K Steinsson, M Khamashta, M Petri, S Manzi, M A Dooley, R
Ramsey-Goldman, R Van Vollenhoven, O Nived, G Sturfelt, C Aranow, K
Kalunian, M Ramos-Casals, A Zoma, J Douglas, K Thompson and V
Farewell

Ann Rheum Dis 2010 69: 529-535 originally published online April 8,
2009
doi: 10.1136/ard.2008.106351

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