Lupus (2007) 16, 418425

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 Alarcn (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 dene 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 denition of cognitive impairment in the ACR nomenclature for neuropsychiatric lupus syndrome was adopted. Cognitive impairment is a decit 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 dened as a decit of 1.51.9 SD below the mean. Focal decline is dened 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 dened as an improvement of 1.0 SD with an effect size of 1.0 in the key domains of the ACR neuropsychological testing, and an improvement of 1.0 SD with an effect size of 1.0 in functional performance of the CSI. Lupus (2007) 16, 418425 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 difculties that are not specic to one brain region or cognitive domain, and in the majority of patients are subclinical.38 Many of these cognitive difculties 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 difcult to determine whether cognitive impairment is related to the disease, its complications, its treatments, or to co-morbid conditions. The ACR Nomenclature and Case Denitions for Neuropsychiatric Lupus Syndromes9 denes 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 uency), reasoning and problem solving, psychomotor speed, and executive functions (eg, planning, organizing and sequencing). The denition 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 decits 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 prole of self-perceived cognitive function in
10.1177/0961203307079044

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Table 1
Conditions

Factors that inuence cognitive function

Causes 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

Cerebral pathology

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 gure 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

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 Conict 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 denitions, 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, SELENASLEDAI, 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 denition 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 nal 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 dened 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 ndings of studies of cognitive impairment in SLE have varied with no consistent pattern of cognitive impairment established.
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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

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The systematic review of relevant literature identied 25 controlled studies out of 142 based on their design and the quality of their execution.1439 Cognitive impairment was dened in most of these studies using criteria designed to be analogous to inferential testing of a two-tailed hypothesis at a signicant level of 0.05. For most of these studies, cognitive impairment was said to be present if the subjects 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 2761% of SLE patients, the variation probably due to differences in patient selection and in case denitions. Mean test scores were signicantly 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 signicant 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 rst group. The most severe levels of impairment were in the domains of attention (16 studies), memory (12 studies), and verbal uency (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. 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 inuenced by the subjects 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
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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 identication 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 lupus1539 and non-lupus patients4448 to screen for cognitive impairment, and follow patients longitudinally. The ACR battery is valid and reliable,19 does not have signicant motor demands and takes about one hour to perform.
Formal functional assessment. This assesses the impact

Neurocognitive tests. Several screening tests identify

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 difculties 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

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(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 sufciently sensitive. Most of prior studies have found no correlation between cognitive impairment and disease activity as measured with any of the instruments mentioned.5,23,3033,39,49 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 ow measurements]5160 and serological markers of cognitive function or brain damage, including antiphospholipid antibodies,6165 antiN-methyl-D-aspartate (NMDA) antibodies14,66 and other biologic markers,14,6671 were considered but the data and the experience with them were insufcient 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 denition of cognitive impairment has not been validated in children. The assessment of neurocognitive functioning in children entails unique challenges that complicate the already difcult problem of determining the presence of clinically signicant 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 difcult to interpret.75 Children tend to have shorter attention spans and be more prone to fatigue than their adult counterparts, negatively inuencing lengthy testing batteries and threatening the validity of test results.76 Moreover, standard denitions 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 denition 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 dened as a score 1.51.9 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 specic 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 dened if improvement of 1.0 SD with an effect size of 1.0 in a key domain or restoration of normal performance in the battery. The Cognitive Symptom Inventory. A clinically important

response is dened if an improvement in functional response with an effect size of

1.0 SD in 1.0.

Table 4 Clinically important response

A) ACR neuropsychological battery A change of 1.0 SD with an effect size of domain B) Cognitive Symptom Inventory A change of 1.0 SD with an effect size of ACR 1.0, better or worse in key

1.0 standard deviation.

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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. Dening 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 benets 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 assessors 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

Test (NART), and Wechsler Adult Intelligence Scale (WAIS). The use of the 42-item questionnaire evaluates nonspecic neurological soft signs that may inuence cognitive performance and correlate with a generalized cognitive decit rather than to any specic cognitive function. Though this questionnaire may be useful occasionally as an indicator of global cerebral dysfunction of various etiologies, it is not used to conrm impression of global impairment or to monitor changes in cognitive functions. A fundamental difculty 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 subjects cognitive decits. To optimize efciency in neurocognitive testing, functional assessment may contribute to the prole 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 Alarcn et al.4 and others,82 the CSI appears not to be affected by the patients 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 signicant 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 signicant 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 rst attempt to dene 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

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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 Dsseldorf, 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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Proposed response criteria for neurocognitive impairment Ad Hoc Committee

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