Lupus (2007) 16, 418–425
http://lup.sagepub.com
PAPER
Proposed response criteria for neurocognitive impairment
in systemic lupus erythematosus clinical trials
Ad Hoc Committee on Lupus Response Criteria: Cognition Sub-committee
Members of the Ad Hoc Committee were J Mikdashi* (Co-Chair), JM Esdaile (Co-Chair), GS Alarcón (Co-Chair), L Crofford,
BJ Fessler, L Shanberg, H Brunner, V Gall, JR Kalden, MD Lockshin, MH Liang, N Roberts Jr and M Schneider
The objective of this study was to identify reliable and valid instruments to measure cognitive
impairment in systemic lupus erythematosus (SLE), and to define minimally important change of
cognitive impairment in SLE for clinical trials. Neurocognitive measures used in randomized clinical
trials in SLE were reviewed, and response criteria were developed using consensus expert opinion.
The definition of cognitive impairment in the ACR nomenclature for neuropsychiatric lupus syndrome
was adopted. Cognitive impairment is a deficit of 2.0 or more standard deviations (SD) below the
mean, compared to normative data, in the key domains of attention, memory and psychomotor speed.
Cognitive decline is defined as a deficit of 1.5–1.9 SD below the mean. Focal decline is defined if
impairment exists in one or more measures within one domain, and multifocal decline if impairment
exists on measures spanning two or more domains. The combination of ACR neuropsychological
battery and the Cognitive Symptoms Inventory (CSI) is recommended to quantitate cognitive
function. A clinically important response is defined as an improvement of ⱖ1.0 SD with an effect size
of 1.0 in the key domains of the ACR neuropsychological testing, and an improvement of ⱖ1.0 SD
with an effect size of 1.0 in functional performance of the CSI. Lupus (2007) 16, 418–425
Key words: clinical trials; cognitive function; cognitive impairment; neuropsychological testing;
response criteria
Introduction
The American College of Rheumatology has begun
initiatives to facilitate clinical trials in systemic lupus
erythematosus (SLE) and to standardize the endpoints
used. Response criteria for six measures of overall disease activity were put forth with the intention that they
be used with measures for principal manifestations targeted in the clinical setting.1 A priori response criteria
for proliferative and membranous renal disease in SLE
has been published,2 and this paper describes the work
in cognitive impairment.
Patients with SLE often complain of cognitive
difficulties that are not specific to one brain region or
cognitive domain, and in the majority of patients are
subclinical.3–8 Many of these cognitive difficulties are
associated with metabolic disturbances, medications or
*Correspondence: Jamal A Mikdashi, University of Maryland School of
Medicine, Division of Rheumatology and Clinical Immunology, 10 S
Pine Street, Suite 834, Baltimore, MD 21201, USA. E-mail: jmikdash@
umaryland.edu
Received 31 October 2006; accepted 13 March 2007
© 2007 SAGE Publications
prior learning disabilities and psychiatric syndromes
(Table 1). In the individual patient it is often difficult
to determine whether cognitive impairment is related
to the disease, its complications, its treatments, or to
co-morbid conditions.
The ACR Nomenclature and Case Definitions for
Neuropsychiatric Lupus Syndromes9 defines cognitive
impairment as a decline from a higher former level of
functioning in one or more of the following domains;
simple or complex attention, memory (eg, learning and
recall), visual-spatial processing, language (eg, verbal
fluency), reasoning and problem solving, psychomotor
speed, and executive functions (eg, planning, organizing and sequencing). The definition for cognitive
impairment in SLE requires documentation by a neurocognitive battery.10,11 The ACR neurocognitive short
battery (Table 2) was suggested to assess cognitive
deficits in SLE and in assessing changes over time.
It is agreed upon that a validated, brief screening
measure could be used to identify patients with SLE
who should be referred for formal neurocognitive evaluation. The Cognitive Symptoms Inventory (CSI)12 provides a profile of self-perceived cognitive function in
10.1177/0961203307079044
Proposed response criteria for neurocognitive impairment
Ad Hoc Committee
419
Table 1 Factors that influence cognitive function
Conditions
Causes
Cerebral pathology
Structural CNS damage (eg, MRI*)
Primary neurological illnesses
History of learning disability
History of head injury
Epileptic seizures
Psychosis
Mania
Depression
Anxiety
Glucocorticoids, narcotic analgesics
Alternative medications (eg, herbs)
Illicit drug use
SLE activity
Comorbid illnesses
aPL** status
Uremia
Diabetes
Others ⫹⫹
Sleep deprivation
Fatigue
Acute or chronic pain
Age/development
Sociocultural factors
Psychiatric disorders
Medications
Toxic disorders
Medical illnesses
Metabolic disturbances
Physiologic conditions
Environmental factors
*MRI ⫽magnetic resonance imaging
**aPL ⫽anti-phospholipid antibodies
⫹⫹⫽electrolyte disturbances or hepatic failure.
Table 2 Cognitive tests of the proposed one-hour repeatable
neuropsychological battery
NART (to estimate IQ)**
Digit symbol substitution test
Trail making test (part A & B)
Stroop color and word test
California verbal learning test
Rey Osterrieth complex figure test (with delayed recall)
WAIS III letter numbering sequencing**
Controlled oral word association test
Animal naming
Finger tapping
*NART ⫽ National Adult Reading Test, IQ ⫽ Intelligence Quotient,
WAIS ⫽Wechsler Adult Intelligence Scale.
**Not appropriate for use in children and adolescents.
rheumatic diseases and assesses self-reported functional
competency in commonly performed activities of daily
living that require cognition. This inventory addresses
functional capabilities that are strongly associated with
other measures of cognitive impairment in SLE.4
Material and methods
The ACR SLE Response Criteria Committee consists
of clinicians, stakeholders and trial methodologists from
the ACR, the Systemic Lupus International Collaborating
Clinics (SLICC) group, the European League Against
Rheumatism (EULAR), the Pan American League
against Rheumatism (PANLAR), the International
League Against Rheumatism (ILAR), the Food and Drug
Administration (FDA) and the Outcome Measures in
Rheumatology Clinical Trials (OMERACT) group.
No industry funding was accepted. All participants signed
Conflict of Interest statements and attested that they met
the standards of ethical conduct of the ACR.
Outcome measures used in cohort studies and randomized controlled clinical trials in SLE were reviewed.
(JAM) using MEDLINE search of the English literature published from January1986 to June 2006; key
words search included SLE, cognition, neuropsychological assessment, and outcome measures. The committee viewed the studies, assessed their quality (accurate
and appropriate outcomes, clear case-control definitions,
blinding, reliable assessment of disease state, appropriate statistical tests used),13 and the psychometric
properties (validity, reproducibility, sensitivity) of
cognitive measures. In addition, subscales of the
SLEDAI, SLEDAI 2K, SELENA–SLEDAI, SLAM,
SLAM-R, ECLAIM and RIFLE were inspected for
their sensitivity for measuring cognition. The SLE
Response Criteria Committee has recognized that the
choice of endpoints and the definition of a meaningful
change have to be, to some degree, arbitrary and based
on consensus expert opinion.
A nominal group exercise was conducted to generate a list of mutually exclusive, collectively exhaustive
covariates that should be reported in studies needed to
interpret the results of neurocognition. A formal vote
was taken to determine those that were felt to represent
minimum essential neurocognitive disease endpoints.
A second exercise was done to establish a consensus
for a minimally important change of the endpoints.
The committee did this without fully acknowledging
that data was lacking to rationalize this choice of biological importance and that this was for the purpose of
standardization.
The final recommendations were sent for review by
invited experts in adult and pediatric rheumatology,
neurology, neuropsychology and clinical epidemiology (see also acknowledgements). Our recommendations were not reviewed by ACR.
Results
A diversity of cognitive abnormalities has been reported
in patients with SLE. The ACR has defined cognitive
impairment as a decline in one or more of the following
domains: simple attention, complex attention, memory,
visual spatial processing, language, reasoning/problem
solving, psychomotor speed and executive function.9
The findings of studies of cognitive impairment in SLE
have varied with no consistent pattern of cognitive
impairment established.
Lupus
Proposed response criteria for neurocognitive impairment
Ad Hoc Committee
420
The systematic review of relevant literature identified 25 controlled studies out of 142 based on their
design and the quality of their execution.14–39 Cognitive
impairment was defined in most of these studies using
criteria designed to be analogous to inferential testing
of a two-tailed hypothesis at a significant level of 0.05.
For most of these studies, cognitive impairment was
said to be present if the subject’s scores were more
than two standard deviations (SD) below the estimated
population mean; this constituted performance for the
bottom 2.5% of the general population. If the population data were not normally distributed, percentiles
were calculated so that those in the lowest 2% were
considered abnormal.
For the 25 studies, cognitive impairment was
reported in 27–61% of SLE patients, the variation
probably due to differences in patient selection and in
case definitions. Mean test scores were significantly
lower in the domains of attention (20 studies), visual
memory (16 studies), verbal memory (15 studies) and
psychomotor speed (13 studies) for SLE patients as
compared to controls. No significant abnormalities
were, noted on measures of language, visual spatial
and concept formation for most of the studies. When
SLE patients who had previously experienced neuropsychiatric SLE were compared to those who have
never had such involvement, severe impairment was
observed among the first group. The most severe levels
of impairment were in the domains of attention (16
studies), memory (12 studies), and verbal fluency (nine
studies).
Neurocognitive assessment
Neurocognitive assessment analyses cognitive and
behavioural disturbances resulting from abnormal brain
development, head trauma, or other disorders.11
Techniques to measure cognitive performances or its
impact were reviewed by the committee.
Table 3
Cognitive symptoms inventory questionnaire*
Dial a telephone
Organize preparing meals at home
Recognize people you know
Learn new things
See different colors only as black and white
Remember details of your recent experiences
Remember important experience in your past
Shop for food or things you need without a list
Manage moneymaking change, pay bills
Remember to take your medications, as you should
Remember details at home or at work
Stay awake during a movie or TV show
Concentrate on a task you need to do
Concentrate on more than one task at a time
Find the correct word during conversations
Remember why you came into a room
Remember where you put things such as keys and glasses
Remember what you ate or wore two days ago
Find your way while driving
Keep track of things to do without a list
The 21 self-report cognitive symptoms inventory questionnaire concerns
possible problems in every day activities over last month. The following is a
score system to each question asked, ranging between never a problem (1),
a problem some of the time (2), a problem most of time (3), a problem all
of time/unable to do (4), and not applicable (0).
*Not appropriate for use in children and adolescents.
qualitative information. The interpretation of test
results and the identification of cognitive impairment
are based on normative data appropriate for age, education, gender and ethnic group.4,8,11
Many neurocognitive test batteries are available and
often require more than one hour to administer. The
battery (Table 2) of the ACR attempts to standardize
and make testing more practical includes components
from other batteries that have been used in lupus15–39
and non-lupus patients44–48 to screen for cognitive
impairment, and follow patients longitudinally. The
ACR battery is valid and reliable,19 does not have significant motor demands and takes about one hour to
perform.
Formal functional assessment. This assesses the impact
Neurocognitive tests. Several screening tests identify
cognitively impaired patients. These include the MiniMental State,40 the Cognitive Capacity Screening
examination41 and the Neurobehavioral Cognitive
Status examination.42 These tests have substantial false
negative rates, do not cover all domains of cognitive
functioning, fail to detect early or milder forms of cognitive impairment, are relatively insensitive to detect
changes overtime, and are influenced by the subject’s
sociodemographic features.
Formal neurocognitive testing assesses cognitive
task performance and provides an objective, comprehensive and non-invasive evaluation of cerebral
functioning.43 These tests are administered and scored
in a standardized fashion and yield quantitative and
Lupus
of cognitive performance on the individuals. Such tests
measure the level of day-to-day functioning indicative
of cognition. The integration of cognitive measures
and functional assessment of social and occupational
domains are important evidence required for the diagnosis of cognitive impairment. The CSI is a selfreported instrument and was felt best used as a screen
for difficulties in daily activities involving intermediate memory, concentration, attention, and executive
function12 to determine the level of assistance the
patient may need, and can be used to monitor changes
that occur over time (Table 3).
The scales of instruments measuring overall disease
activity reviewed by the committee included SLEDAI
and SLEDAI-2K the Systemic Lupus Activity Measure
Proposed response criteria for neurocognitive impairment
Ad Hoc Committee
421
(SLAM, SLAM/R), the British Isles Lupus Assessment
Group (BILAG), the European Consensus Lupus
Activity Measurement (ECLAM), and the Response
Index For Lupus Erythematosus (RIFLE). The committee felt coverage of cognitive function by these
scales was not sufficiently sensitive. Most of prior
studies have found no correlation between cognitive
impairment and disease activity as measured with any
of the instruments mentioned.5,23,30–33,39,49 Similarly,
most studies found no correlation between
SLICC/ACR damage index (SDI) scores and cognitive
impairment.4,16,24,25,50 Neuroimaging technique [computed tomography, conventional magnetic resonance,
magnetic resonance spectroscopy, magnetization
transfer imaging, single photon emission computed
tomography (SPECT), positron emission tomography
(PET), cerebral blood flow measurements]51–60 and
serological markers of cognitive function or brain
damage, including antiphospholipid antibodies,61–65
anti–N-methyl-D-aspartate (NMDA) antibodies14,66
and other biologic markers,14,66–71 were considered but
the data and the experience with them were insufficient
to judge their sensitivity to change and their prognostic value. Moreover an indeterminate number of SLE
patients with and without cognitive impairment have
these markers.
Assessment of neurocognitive functioning
in children with SLE
Neurocognitive involvement in pediatric SLE is an
important problem.72,73 In a small cohort study children with SLE were found to have more problems
acquiring new cognitive skills when compared to their
peers.74 The ACR definition of cognitive impairment
has not been validated in children. The assessment of
neurocognitive functioning in children entails unique
challenges that complicate the already difficult problem of determining the presence of clinically significant cognitive impairment due to SLE. Furthermore,
both testing techniques and aspects of normal cognitive function, change dramatically with age and development, making serial testing more difficult to
interpret.75 Children tend to have shorter attention spans
and be more prone to fatigue than their adult counterparts, negatively influencing lengthy testing batteries
and threatening the validity of test results.76 Moreover,
standard definitions for test interpretation in children
must consider age related normative data. Accordingly,
available assessment instruments may not be applicable across the entire age range of children diagnosed
with SLE.
Despite the apparently high prevalence of neurocognitive involvement in pediatric SLE,72 there are
no large published studies addressing the usefulness
of available neurocognitive assessment instruments in
these populations. However, initial validation studies
of the pediatric version of the ANAM suggest this tool
may be useful for assessing cognitive functioning of
children as young as eight years of age in a clinical
setting.77 Finally, preliminary evidence suggests that
self report of subjective cognitive symptoms in children is unreliable to screen for neurocognitive dysfunction, in sharp contrast to what has been shown in
adults.72
Recommendations of the committee
The committee uses the ACR definition of cognitive
impairment. Cognitive impairment is said to present
if the score is 2.0 or more SD below the mean in key
domains of attention, memory, and psychomotor speed,
compared to normative data using the ACR neurocognitive battery, whereas, cognitive decline is defined as a
score 1.5–1.9 SD below the mean. Cognitive impairment is considered focal if one or more measures within
one domain are affected and multifocal when measures
spanning two or more domains are affected.
The committee recommends the ACR neurocognitive battery and the CSI be used in studies directed at
therapeutic or rehabilitative strategies. These instruments may be used to screen for cognitive impairment
in SLE and to follow patients longitudinally. However,
it should be noted that we could not identify any specific study of whether longitudinal monitoring is useful
prognostically or therapeutically. The current recommendations are only appropriate for the assessment of
neurocognitive impairment in adults with SLE.
Clinically important response (Table 4)
The ACR neurocognitive battery. A clinically important
response is defined if improvement of ⱖ1.0 SD with
an effect size of ⱖ1.0 in a key domain or restoration of
normal performance in the battery.
The Cognitive Symptom Inventory. A clinically important
response is defined if an improvement in ⱖ1.0 SD in
functional response with an effect size of ⱖ1.0.
Table 4
Clinically important response
A) ACR neuropsychological battery
A change of ⱖ1.0 SD with an effect size of ⱖ1.0, better or worse in key
domain
B) Cognitive Symptom Inventory
A change of ⱖ1.0 SD with an effect size of ⱖ1.0
ACR ⫽American College of Rheumatology. SD ⫽standard deviation.
Lupus
Proposed response criteria for neurocognitive impairment
Ad Hoc Committee
422
Discussion
The conduct of clinical trials of interventions where
neurocognitive SLE is the therapeutic target is challenged by the heterogeneity of SLE patients with cognitive impairment, the various patterns of cognitive
abnormalities observed, and the lack of surrogate
markers. Defining standardized clinical response criteria for cognitive impairment in SLE allows the testing
of new therapeutic approaches and permits the pooling
of data and comparison of results across SLE populations. These tools can also be used to measure side
effects of medications, sleep disturbance, fatigue and
other factors which are known to affect cognitive
performance.
The committee has addressed various neurocognitive tools including the computer-administered test
battery (automated neuropsychological assessment
metrics — ANAM)8,14,50 and the 42-item questionnaire
adapted by Denburg et al.78 Beyond ease of administration and data collection, the computer-based assessment offers other benefits over paper-and-pencil
testing in the form of millisecond timing accuracy, reliable and randomized presentation of stimuli over multiple trials and repeat administrations, and unobtrusive
measurement of cognitive skills and response times
during the assessment process. Therefore, this instrument may be particularly useful for longitudinal
assessment of change. However, the use of the automated neurocognitive testing is limited with respect to
predicting the nature and the extent of cognitive
impairment, and lacking the degree of sophistication
necessary to produce the same results as a human
assessor’s professional judgment that combines test
data with other pertinent clinical variables.79 Thus, the
advantages and disadvantages of computerized methods must be considered, in anticipation of the development of psychometric data based on comparisons with
long-standing empirically sound test measures, and the
use of computerized adaptive testing tailored towards
SLE patients.
Assessment of neurocognitive functioning in children and adolescents with SLE requires consideration
of the developmental stage and age of the child. As a
result, standardized testing batteries for children may
require additional measures and more time to complete
than those for adult patients. An ongoing effort by the
Childhood Arthritis and Rheumatology Research
Alliance (CARRA) will lead to consensus on a suitable
standardized pediatric SLE neurocognitive battery;
however, the evidence required for such recommendations does not exist at this time. Nevertheless, several
of the tests recommended for adults in these guidelines
are known to be inappropriate for children and adolescents, including the CSI, National Adult Reading
Lupus
Test (NART), and Wechsler Adult Intelligence Scale
(WAIS).
The use of the 42-item questionnaire evaluates nonspecific neurological soft signs that may influence cognitive performance and correlate with a generalized
cognitive deficit rather than to any specific cognitive
function. Though this questionnaire may be useful
occasionally as an indicator of global cerebral dysfunction of various etiologies, it is not used to confirm
impression of global impairment or to monitor changes
in cognitive functions.
A fundamental difficulty with cognitive testing is
the control of independent variables, which sometimes
can be addressed by grouping patients according to
the clinical manifestations of neuropsychiatric SLE,
socio-demographic status or adjusting for co-morbidities.
However, it is important to recognize that individuals
grouped in this fashion might not necessarily exhibit
similar patterns of cognitive impairment.80,81
A critical component in the diagnosis of mild cognitive impairment is to determine whether every day
functioning is impacted by the subject’s cognitive
deficits. To optimize efficiency in neurocognitive testing, functional assessment may contribute to the profile
of cognitive impairment. Our Committee recommends
the use of the CSI, as indicative of cognitive function,
for the screening patients suspected of having cognitive impairment in the research and clinical settings.
As noted by Alarcón et al.4 and others,82 the CSI
appears not to be affected by the patient’s sociodemographic background. However, it is necessary to
establish the psychometric properties of the CSI; validation studies must examine the relationship between
the patients’ CSI scores and their performance on the
ACR neurocognitive battery.
The goal of most studies of cognitive function in
patients groups is to demonstrate that a decline in
function has reached a level such that it provides a
statistically significant difference between the performance of the patient and control groups. Determining
what constitutes a real change between tests or following an intervention relies heavily on the reliability
and validity of the psychometric tests, but most
importantly on what is regarded as clinically significant or meaningful change. However, in clinical
trials, it is not always evident that statistically significant differences in cognitive function are clinically
important.
Although much work remains, this is the first
attempt to define response criteria for clinical trials for
cognitive impairment in SLE. The ACR neurocognitive battery and the CSI assess all major areas of cognitive function and are suitable for individual patients.
Because of heterogeneity and comorbidities, subanalysis should be based on segregating patients into
Proposed response criteria for neurocognitive impairment
Ad Hoc Committee
423
groups emphasizing the complexity of neurocognitive
complications in SLE. Further research should be
devoted to validate these measures in randomized
clinical trials and longitudinal observational studies,
and to identify biological markers and, possibly,
neuroimaging techniques in the measurement of
response.
Acknowledgements
We gratefully acknowledge the logistical and staff
support of Ms Amy Miller, the secretarial contribution
of Ms Angela Strickland and the invaluable input from
Dr Robin Brey, Dr Melanie Harrison, Dr Lynn Grattan,
Dr Deborah M Levy, Dr Kelly Anthony and Dr Marisa
Klein-Gitelman.
Supported by grants from the American College
of Rheumatology, a Kirkland Scholar Award, the SLE
Foundation of New York, The Lupus Erythematodes
Selbsthilfegemeinschaft e. V. Germany, NIH Grant
number AR47782, R13 AR47584-01, Robert B.
Brigham Arthritis and Musculoskeletal Diseases
Clinical Research Center (Harvard University), the
Heinrich-Heine-University in Düsseldorf, the Arthritis
Research Centre of Canada (University of British
Columbia), the Massachusetts Veterans Epidemiology
Research and Information Center, and the Center for
Advanced Methodological Support for Innovative SLE
Clinical Trials (ASSIST).
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