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Measurement of fatigue in systemic lupus erythematosusA systematic review.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 57, No. 8, December 15, 2007, pp 1348 –1357
DOI 10.1002/art.23113
© 2007, American College of Rheumatology
Measurement of Fatigue in Systemic Lupus
Erythematosus: A Systematic Review
Objective. To systematically review fatigue instruments used in patients with systemic lupus erythematosus (SLE) and
to seek consensus on which instruments should be recommended for future studies and which data on comorbid
conditions should be reported when evaluating fatigue in patients with SLE.
Methods. We used data from Medline and EMBase databases (from January 1970 to June 2006), clinical experts, and
bibliographies. Data were extracted independently by 4 authors and reviewed by a working group and larger expert panel
to produce a recommendation. Instruments were examined for construct validity, reliability, and responsiveness to
change. Correlations between fatigue and some components of the Medical Outcomes Study Short Form 36 (SF-36),
disease activity, and comorbidities were reviewed.
Results. We identified 34 studies that used 15 fatigue instruments in patients with SLE. The Fatigue Severity Scale (FSS)
was used in 56% of the studies. The Systemic Lupus Activity Measure was significantly correlated with fatigue, but the
Systemic Lupus Erythematosus Disease Activity Index was not. Fatigue was also correlated with pain, poor quality of
sleep, depression, and with each subscale of the SF-36.
Conclusion. The working group and expert panel recommend the 9-item FSS for evaluating fatigue in SLE patients.
Responsiveness to change of fatigue instruments has not been well established in SLE and needs further study. The panel
suggested that an important improvement or response could be a 15% decrease in the FSS. The effect of several important
confounding factors of fatigue such as sleep disorders, depression, fibromyalgia, and anemia needs to be collected and
KEY WORDS. Systemic lupus erythematosus; Fatigue; Fatigue Severity Scale; Systemic Lupus Activity Measure; Systemic
Lupus Erythematosus Disease Activity Index.
Systemic lupus erythematosus (SLE) can affect any organ,
including skin, kidney, lung, brain, heart, and joints.
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, the NIH (grants AR-47782 and R13AR-47584-01), the 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, the Center for Advanced
Methodological Support for Innovative SLE Clinical Trials,
the CONACYT (Mexico), the Canadian Arthritis Network,
the Michael Smith Foundation for Health Research, and the
Canadian Institutes for Health Research.
Members of the Ad Hoc Committee on SLE Response Criteria for Fatigue are as follows: J. Antonio Aviña-Zubieta,
MD, MSc: Arthritis Research Centre of Canada, Vancouver,
British Columbia, Canada; Graciela S. Alarcón, MD: University of Alabama at Birmingham; Heike A. Bischoff-Ferrari, MD, MPH: Boston University School of Medicine, Boston, Massachusetts; Rebecca Fischer-Betz, MD, Matthias
Therefore, clinical manifestations are broad and variable
in severity. In clinical management and research of patients with SLE, objective parameters are used to describe
disease activity and treatment efficacy. In addition, there
Schneider, MD: Heinrich-Heine-University, Düsseldorf,
Germany; Victoria Gall, MD, Matthew H. Liang, MD, MPH,
Peter Schur, MD: Brigham and Women’s Hospital, Boston,
Massachusetts; Gabor Illei, MD: NIH, NIDCR, Bethesda,
Maryland; Jamal Mikdashi, MD: University of Maryland,
College Park; Michelle Petri, MD, MPH: Johns Hopkins
School of Medicine, Baltimore, Maryland; Charlotte Phillips, RN, MPH, CCRC: New England Baptist Hospital, Boston, Massachusetts; Jacques Pouchot, MD: European
Georges Pompidou Hospital, Paris, France; William
St.Clair, MD: Duke University Medical Center, Durham,
North Carolina.
Drs. Aviña-Zubieta and Bischoff-Ferrari and Ms Phillips
contributed equally to this work.
Dr. Bischoff-Ferrari received consultant fees and speaking
fees (less than $10,000 each) from Merck Sharp & Dohme,
Novartis, and Amgen. Dr. St.Clair received consultant fees
(less than $10,000) from Medimmune, Human Genome Sciences, Novartis, Bristol-Myers-Squibb, Synovex, and Genentech.
SLE and Fatigue
are some subjective parameters that are also important for
the patients since these have an impact on their quality of
life. Among these subjective parameters, fatigue is the
most prevalent symptom in SLE, since it is present in up to
90% of the patients (1). Moreover, ⬃50% of the patients
consider fatigue the most disabling disease symptom (2).
Despite its high prevalence and its impact on quality of
life, fatigue has not been well studied in patients with SLE.
An important problem with fatigue is its definition and
therefore its measurement. In the literature there are numerous ambiguous and inconsistent definitions for fatigue,
which vary between research studies, including those evaluating fatigue in a single condition such as cancer-related
fatigue (3). This is a major problem since some instruments
only measure physical fatigue through limitation on daily
living activities. Others also consider mental fatigue and its
associated distress. Thus, level of fatigue and its impact on
quality of life depends on the instrument used to measure it
and the conceptualization of fatigue.
In SLE, the origin of fatigue is often multifactorial and
could be mediated through comorbid conditions (depression, sleep disorder, fibromyalgia [FM]), behavioral factors
(physical activity), and disease-related factors (disease activity, treatment). Among comorbid conditions, depression has
been consistently demonstrated to be associated with fatigue
in patients with SLE (2,4 – 6). The coexistence of FM has been
proposed as a contributor to persistent fatigue in patients
with SLE, or at least as an influence to the perception of
fatigue (7). Other studies have demonstrated that the association between fatigue and FM is related to the number of
tender points, with higher fatigue scores seen in patients who
satisfy the American College of Rheumatology criteria for FM
(8) than in those who do not (4,9 –11).
Behavioral factors such as poor exercise participation
have been associated with fatigue, and interventions in
this area have demonstrated a positive impact on fatigue
(12,13). Finally, disease activity has been one of the most
widely studied contributors of fatigue in SLE. However,
the results are conflicting; some studies showed a significant correlation between disease activity and fatigue
(4,6,14,15) while others showed either no or weak associations (1,5,16).
There are several validated instruments to measure fatigue and many have been used in SLE patients (2,3,17–
27). To date, there has been no consensus on which instrument should be used in the assessment of fatigue in SLE,
and how to favorably affect it. Our working group and
expert panel convened an Ad Hoc Committee on SLE
Response Criteria for major organ involvement and key
manifestations, to make recommendations for clinical trials in patients with SLE.
The aim of this ad hoc committee was to perform a
systematic review of the literature on fatigue instruments
Address correspondence to J. Antonio Aviña-Zubieta,
MD, MSc, Arthritis Research Centre of Canada, 895 West
10th Avenue, Vancouver, British Columbia, V5Z 1L7, Canada. E-mail:
Submitted for publication December 21, 2006; accepted in
revised form June 7, 2007.
used in SLE. Based on quality criteria, including construct
validity, reliability, and responsiveness, the panel recommended instruments or a combination of instruments for
use in future studies of patients with SLE, and also made
recommendations on whether to develop new instruments. A consensus on which instrument or instruments
should be used to measure fatigue in SLE would allow
improved efficiency in future research by allowing comparisons across studies. The panel also identified important covariates that are strong correlates of fatigue in patients with SLE, and made recommendations on what
factors should be measured and reported.
Search strategy. We conducted a systematic review of
all English language publications using the Medline and
EMBase electronic databases from their inception (1966
and 1980, respectively) to July 2006. We included all intervention studies and observational studies in which a
self-reported measurement of fatigue was applied to patients with SLE. In addition, clinical experts were contacted and bibliographies of existing publications were
reviewed. MeSH terms (medical subject headings) included fatigue (fatigue/or fatigue syndrome, chronic/or
mental fatigue/or muscle fatigue) and lupus (lupus/or lupus erythematosus, systemic/or lupus erythematosus, discoid/or lupus nephritis). Data abstraction was conducted
by 4 investigators (JAA-Z, CP, HAB-F, and JP).
Analysis and consensus on scale validation. The consensus process involved 3 steps. First, the data were extracted and summarized by 2 investigators (CP and HABF). Second, the working group and expert panel committee
met at Heinrich-Heine-University, Düsseldorf, Germany
from May 9 –12, 2002. The working group discussed the
collected data on fatigue instruments in SLE. Third, once
the working group reached a consensus, their findings
were presented to the larger expert panel. The final consensus is presented below.
The main psychometric properties (construct validity,
reliability, and responsiveness to change) were evaluated
using the original article describing the validity of the
instrument. Psychometric properties were described as either present or absent. We sought to identify a single
fatigue instrument that was optimal, based on these criteria. Studies that assessed fatigue in SLE were screened for
additional comorbid factors that needed to be evaluated in
the context of fatigue in SLE. These factors were sleep
disorder, depression, FM, and anemia, as well as medications that may cause fatigue. Of further interest, we looked
for the correlations between fatigue and some components
of the Medical Outcomes Study Short Form 36 (SF-36), an
extensively used measure of health-related quality of life
(23). The SF-36 covers 8 domains of health status, including physical functioning, role physical, role emotional,
social functioning, bodily pain, mental health, vitality,
and general health. Scores in each domain range from
0 –100, where higher scores reflect better performance or
better quality of life. We calculated pooled summary esti-
Aviña-Zubieta et al
Table 1. Fatigue instruments used in studies of patients with systemic lupus erythematosus (SLE)*
Instrument (ref)
FSS (2)
ChFS (18)
MAC-FS (19)
PFS (20)
SF20⫹1 (21)
FSES (22)
SF-36-V (23)
MAF (24)
MFI-20 (44)
Fatigue rating (15)
VAS for fatigue (25)
FAI (26)
VAS-fatigue (41)
SBPI (27)
Single question for
fatigue (10)
Measures fatigue impact on specific
types of functioning
Measures severity of fatigue in 2
dimensions (mental, physical)
Assesses stamina, energy, and tiredness
Measures fatigue in 4 subscales
(temporal, severity, affective,
SF-20 plus 1 added fatigue question
Assesses confidence in controlling
4-item measure of vitality (energy level
and fatigue)
Measures 5 domains of degree, severity,
distress, impact on activities of daily
living, and timing
20-item self-report that generates 5
dimensions of 4 items each (general,
physical, reduced activity, reduced
motivation, mental fatigue)
Self-report of fatigue after strenuous,
regular, or mild activity
4 VAS to measure different aspects of
fatigue (mental, physical, exertional
mental, exertional physical)
Expanded version of the FSS
evaluating 4 dimensions of fatigue
(severity, situation-specificity,
psychological consequences,
response to rest/sleep)
100-mm line to measure severity of
3 dimensions (somatic fatigue, mental
fatigue, and general discomfort) with
several facets in each one. Designed
to measure fatigue in Sjögren’s
Presence or absence of fatigue daily in
the last 3 months
Rating/scale direction†
1–7 per item/negative
No. of SLE
No. of
0–4 per item (0⫽never, 1⫽rarely,
2⫽sometimes, 3⫽often,
0–10 per item/positive
0–100 per item/negative
1–4 per item/positive
1–6 per item/positive for items 1,
2 and negative for items 3, 4
1–5 per item (from agreement to
0–100 per item/positive
1–7 per item/negative
1–7 per item/positive
* FSS ⫽ Fatigue Severity Scale; ChFS ⫽ Chalder Fatigue Scale; MAC-FS ⫽ Robert B. Brigham Multipurpose Arthritis Center-Fatigue Scale; PFS ⫽ Piper
Fatigue Scale; SF20⫹ 1 ⫽ Short Form of the Medical Outcome Study questionnaire plus 1 item for fatigue; FSES ⫽ Fatigue Self-Efficacy Scale;
SF-36-V ⫽ Short Form-36 vitality subscale; MAF ⫽ Multidimensional Assessment of Fatigue; MFI-20 ⫽ Multidimensional Fatigue Inventory (20 items);
VAS ⫽ visual analog scale; FAI ⫽ Fatigue Assessment Instrument; SBPI ⫽ Sjögren’s-Based Psychometric Instrument.
† Positive direction ⫽ the higher the value the greater the fatigue; negative direction ⫽ the higher the score the less the fatigue.
‡ Number of SLE studies that applied the instrument from January 1970 to June 2006.
§ Number of citations of study from 1966 for Medline and 1980 for EMBase to July 15, 2006.
¶ NA ⫽ not assessed, multiple citations for the instrument, but not all were for fatigue studies.
mates of correlation coefficients between the Fatigue Severity Scale (FSS) (2) and several domains of the SF-36
using the random effects model, and tested for heterogeneity using the bootstrap version of the Q statistic. All
analyses were done using HePIMA software (28) with adjustment for correlations.
Ad hoc committee participants. The Ad Hoc Committee
consisted of clinicians and trial methodologists from the
American College of Rheumatology, Systemic Lupus International Collaborating Clinics, The European League
Against Rheumatism, Pan American League of Associations for Rheumatology, International League of Associations for Rheumatology, Food and Drug Administration,
and Outcome Measures in Rheumatoid Arthritis Clinical
Trials. Most of the authors of this article were members of
the working group on fatigue in SLE.
We reviewed 15 fatigue instruments that were used in 34
studies with SLE patients (1,2,4 –7,9 –17,19,21,22,26,27,
1 for fatigue
4 for vitality
Fatigue rating
1 item
No. items
General fatigue, PhF,
reduced activity,
reduced motivation,
Fatigue (pervasive
and postexertional
PhF and MF)
Fatigue subscale
Severity, distress,
timing, interference
Vitality (energy,
Physical fatigue (PhF)
Mental fatigue (MF)
Sensory, affective
meaning, cognitive/
mood, behavioral/
Fatigue (1 item)
Self-efficacy for
controlling fatigue
RP/111, CFS/357, PS/481,
MD/158, AR/326
General population/2,450
Breast cancer surviors/328
MS/25, SLE/29, healthy/20,
NR/274, CA/100
Population used to
From 0.86 for
0.84 for PhF, 0.82
for MF
Cronbach’s ␣
FSS (0.6), ChFS (0.6)
VAS-fatigue (0.23,
SF-36 (0.60)
FSS (⫺0.55), AIMS2
physical scale
(⫺0.40), affect
(⫺0.44), PPCS
Factor analysis SF36 physical (0.59),
SF-36 mental
(0.57), general
health (0.65),
quality of life
(0.45), NHP
(⫺0.33, ⫺0.58),
SF20⫹1 (0.6)
POMS-F (0.78),
POMS-V (0.60)
SF-36, CES-D
VAS (0.68), CES-D
CIS-R, ROC analysis
Construct validity
Table 2. Psychometric properties of the fatigue instruments used in studies of patients with systemic lupus
erythematosus (SLE)*
Paired t-test, P ⫽
⬍ 0.0001
Paired t-test, P ⬍ 0.05
Paired t-test, P ⬍ 0.01
SLE and Fatigue
Fatigue severity,
fatigue situationspecificity, fatigue
fatigue response to
Somatic fatigue, MF,
general discomfort
PSS/18, RA/18, SLE/11
Lyme/35, CFS/46, SLE/47,
MS/40, dysthymia/13,
Factor 1 (0.92),
Factor 2 (0.76),
Factor 3 (0.70),
Factor 4 (0.85)
Cronbach’s ␣
SF-36 (⫺0.53, 0.70
among domains)
HAD (0.36, 0.45)
(⫺0.60, 0.69)
RVI (0.4, 0.7)
ES (0.4)
Construct validity
* MS ⫽ multiple sclerosis; CES-D ⫽ Center for Epidemiologic Studies Depression Scale; NR ⫽ new registrations (hospital); CA ⫽ consultant attendants; CIS-R ⫽ Check Individual Strength-revised;
ROC ⫽ relative operating curve; NA ⫽ not available; SF-36 ⫽ Short Form-36 items; AIMS2 ⫽ Arthritis Impact Measurement Scales 2; PPCS ⫽ Patient-Physician Communication Scale; NHP ⫽ Nottingham
Health Profile; VFS ⫽ Vanderbilt Fatigue Scale; RA ⫽ rheumatoid arthritis; POMS ⫽ Profile of Moods States (F-fatigue V-vitality); RP ⫽ radiotherapy patients; CFS ⫽ chronic fatigue syndrome; PS ⫽
psychology students; MD ⫽ medical students; AR ⫽ army recruits; DFA ⫽ discriminant function analysis; RVI ⫽ Rand Vitality Index; ES ⫽ Enervation Scale; HAD ⫽ Hospital Anxiety and Depression
Scale; PSS ⫽ Primary Sjögren’s Syndrome; WHOQOL-BREF ⫽World Health Organization’s Multicultural Quality of Life Instrument, brief form. See table 1 for additional definitions.
† As available.
for fatigue
No. items
Population used to
Table 2. Psychometric properties of the fatigue instruments used in studies of patients with systemic lupus erythematosus (SLE)* (Continued)
Aviña-Zubieta et al
SLE and Fatigue
Table 3. The Fatigue Severity Scale
1. My motivation is lower when I am fatigued.
2. Exercise brings on my fatigue.
3. I am easily fatigued.
4. Fatigue interferes with my physical functioning.
5. Fatigue causes frequent problems for me.
6. My fatigue prevents sustained physical functioning.
7. Fatigue interferes with carrying out certain duties and
8. Fatigue is among my three most disabling symptoms.
9. Fatigue interferes with my work, family, or social life.
* Individuals choose a number from 1 to 7 (where 1 ⫽ strongly
disagree and 7 ⫽ strongly agree). Scale is copyrighted and reproduced with permission.
29 – 43). Table 1 shows the distribution of all identified
fatigue instruments applied in patients with SLE. The majority of the studies (19 [56%] of 34) used the FSS (2). One
study used the Fatigue Assessment Instrument (FAI),
which is an expanded version of the FSS and includes 29
items instead of the original 9 (26). In contrast with the
FSS, the FAI is a multidimensional instrument that measures and differentiates normal fatigue from fatigue related
to medical disorders, and clearly defines fatigue in order to
promote consistency across respondents. In addition to
being the most frequently used, the FSS was also the
instrument with the highest number of citations among all
fatigue instruments. The FSS was developed and tested on
patients with SLE and differentiates patients from controls. Finally, the FSS is one of the few instruments where
responsiveness has been evaluated in patients with SLE.
These were some of the criteria that led the panel to
recommend the FSS for future trials in SLE patients.
Table 2 provides a descriptive summary of all fatigue
instruments used in patients with SLE and also shows
some of the general psychometric properties for each instrument. Construct validity was not evaluated in all studies, especially those that used a single item to measure
fatigue. The FSS, FAI, and Robert B. Brigham Multipurpose Arthritis Center-Fatigue Scale were the only instruments that have been evaluated for reliability and responsiveness in patients with SLE (Table 2).
The 9-item FSS measures the impact of fatigue on specific types of functioning in the previous 2 weeks (Table 3).
This instrument was originally developed with SLE patients, and a normative range has been established (an FSS
score ⬍4 is considered normal). The FSS has been translated from English (US) and adapted into several languages
and populations, including English-speaking countries
(UK, Australia, New Zealand, Canada), Spanish (Mexico,
Spain), French (France, Canada), German (Germany, Switzerland), Chinese (Taiwan), and Portuguese (Brazil).
Table 4 shows the construct validity for most of the
fatigue instruments that have been evaluated in SLE patients. The majority of studies included a validated disease
Table 4. Correlations of fatigue instruments with comorbidities*
Instrument (ref)
FSS (1)
FSS (16)
FSS (22)
FSS (38)
FSS (5)
FSS (40)
Fatigue rating (15)
MAC-FS (19)
SF-20⫹1 (21)
SF-36 (24)
MFI (9)
VAS (7)
Disease activity
Pain (instrument)
Sleep (instrument)
0.53 (SLAM)†
0.37 (SLAM)†
0.40 (ECLAM)†
0.27 (SLAM)‡
0.26 (SLAM)†
0.22 (SLEDAI)
0.16 (SLEDAI)
0.3 (physician rating)
0.49 (BILAG)‡
0.31 (BILAG)‡
0.22 (BDI)‡
0.59 (CES-D)†
0.49 (HAD)‡
0.46 (PSQI)‡
0.35 (VAS-pain)
0.28 (CES-D)†
0.46 (CES-D)‡
0.14 (CES-D)
0.54 (AIMS2-pain)†
0.74 (VAS-pain)†
⫺0.60 (SPI)
0.47 (CES-D)‡
0.52 (CES-D)‡
0.41 (PAQI)‡
0.49 (BDI)‡
0.45 (PSQI)‡
0.26 (SLAM)†
0.02 (SLAM)
0.13 (SLEDAI)
* FSS ⫽ Fatigue Severity Scale; NA ⫽ not applicable; BDI ⫽ Beck Depression Inventory; SLAM ⫽ Systemic Lupus Activity Measure; CES-D ⫽ Center
for Epidemiologic Studies Depression Scale; ECLAM ⫽ European Consensus Lupus Activity Measure; HAD ⫽ Hospital Anxiety and Depression Scale;
PSQI ⫽ Pittsburgh Sleep Questionnaire Index; VAS ⫽ visual analog scale; SLEDAI ⫽ Systemic Lupus Erythematosus Disease Activity Index; AIMS2 ⫽
Arthritis Impact Measurement Scales 2; BILAG ⫽ British Isles Lupus Assessment Group; MAC-FS ⫽ Robert B. Brigham Multipurpose Arthritis Center
Fatigue Scale; SF-20⫹1 ⫽ Short Form of the Medical Outcomes Study questionnaire plus 1 item; SF-36 ⫽ Short Form 36; SPI ⫽ Sleep Problem Index;
MFI ⫽ Multidimensional Fatigue Inventory; PAQI ⫽ Pittsburg Anxiety Questionnaire Index.
† P ⬍ 0.01
‡ P ⬍ 0.001
activity index. The specific instruments for disease activity were the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (45), Systemic Lupus Activity Measure (SLAM) (46), European Consensus Lupus Activity
Measure (47), British Isles Lupus Assessment Group (48),
and a Mexican version of the SLEDAI (49). The depression
scales used were The Center for Epidemiological Studies
Depression Scale (50), the Beck Depression Inventory (51),
the Hospital Anxiety and Depression Scale (52), the Minnesota Multiphasic Personality Inventory (53), and the
Pittsburgh Sleep Quality Index to evaluate sleep (54).
Some studies evaluated the correlations between fatigue
and comorbidities, including disease activity, depression,
pain, sleep disorders, and anemia (Table 4). The SLAM
(without fatigue) was significantly correlated with fatigue
in all studies. On the contrary, the SLEDAI did not correlate with fatigue. All but 1 study identified a positive
correlation between fatigue and depression. In addition,
fatigue was also correlated with pain. Sleep disorder was
assessed in only 15% of the studies, however all agreed
that patients with poor quality of sleep have increased
levels of fatigue (4,6,11,34,39). Moreover, SLE patients
with FM had sleep fragmentation and poorer quality of
sleep compared with patients without FM. In addition,
SLE patients with FM experienced higher levels of fatigue
The single and pooled correlations between the FSS and
depression, helplessness, pain from SLE, and the SF-36
domains are shown in Figure 1. Fatigue was correlated
with each domain in all studies. When testing for heterogeneity among the different pooled correlations, the depression, general health, mental functioning, and vitality
subscales were statistically significant, suggesting that
combining the studies would not be appropriate. However,
the pattern and direction of the studies measuring the
same outcomes were homogeneous, suggesting that the
construct of the FSS is valid.
No studies evaluating response criteria or patients’ perspectives on fatigue were identified. The panel proposed
by consensus that an improvement or response of ⱕ15%
decrease in the FSS should be considered clinically important, but further research in this area will be needed to
test this recommendation.
Fatigue is usually clinically important, although it is a
subjective and nonspecific characteristic in patients with
SLE as well as those with other chronic diseases. The word
fatigue originated based on the experience of healthy individuals, but interview-based studies have revealed that
even though patients label their sensation as fatigue, they
often find it qualitatively very different from the fatigue
they experienced before they became sick (55). This suggests that fatigue may not always be accurately described
on a simple continuum from no fatigue to severe fatigue.
Dittner et al described and evaluated 30 different scales
and concluded that further validation is needed for all
scales and no single scale is appropriate for measuring
fatigue in all disease groups (56). A recent bibliographic
Aviña-Zubieta et al
study of fatigue instruments (57) identified 252 different
ways to measure fatigue, of which 150 ways were used
only once, and only 71 scales were specifically designed to
measure fatigue.
Since there is little consensus on which scales possess
the most attractive properties, it may be useful to know
which scales are actually used to measure fatigue in patients with SLE. Our purpose was to evaluate the available
literature on the topic in order to provide a recommendation for future use in patients with SLE.
The high prevalence and relative importance of fatigue
in patients with SLE is one argument for the need for its
systematic assessment. However, fatigue has not been assessed in a standardized way using a common instrument
nor have cormobid conditions that may mediate fatigue
been assessed. We identified 15 different instruments used
to measure fatigue in SLE. The most commonly used and
cited was the FSS. Moderate and consistent correlations of
fatigue with the 8 subscales of the SF-36, including physical functioning, role physical, role emotional, social functioning, bodily pain, mental health, vitality, and general
health, have been documented (1). The pattern and direction of the studies measuring these outcomes were homogeneous, suggesting that the construct of the FSS is valid
and best evaluated in patients with SLE. In addition, several associations of fatigue with some comorbidities have
also been reported, including disease activity, depression,
pain, and sleep disorders. However, the relationship between fatigue and disease activity is controversial and
research in this area is complicated by the fact that SLAM,
1 of the 2 commonly used disease activity measures, includes fatigue as a component score. None of the studies
that used the SLEDAI found an association with fatigue. In
contrast with the SLAM, the SLEDAI was designed to
measure only inflammatory activity in patients with SLE,
therefore items that may include patient perception (e.g.,
fatigue) are not included, and this could explain the observed differences. Nevertheless, when the fatigue component of the SLAM was removed, the association became
weaker, suggesting that the relationship between fatigue
and disease activity is neither strong nor linear (4).
The most common potential source of fatigue, sleep
disorder, has been assessed in 15% of the SLE studies that
measured fatigue. Medications that may cause fatigue were
not assessed in any study, FM was assessed in only 5
(14%), and depression assessed in 9 (26%) of the studies.
This is a limitation that the panel thought should be addressed in future studies. The panel believed that a future
assessment of comorbid conditions associated with fatigue
in patients with SLE was necessary to gain a complete
understanding of the pathogenesis of fatigue in order to
develop effective treatment strategies.
There are some limitations of this study. First, our current understanding of fatigue’s construct in patients with
SLE has not been well defined and, therefore, it is not clear
which clinical, biologic, or social factors are the most
important contributors to or predictors of fatigue. Second,
although correlations among different fatigue instruments
have been reported in SLE patients (4,13,34), not all instruments measure the same attribute, and direct comparison among instruments was not directly evaluated. Third,
SLE and Fatigue
Figure 1. Study-specific (open squares) and pooled correlations (solid diamonds) between
the Fatigue Severity Scale and A, the general health, bodily pain, vitality, physical functioning, and mental functioning subscales of the Short Form 36, and B, the role physical,
social functioning, and role emotional subscales of the Short Form 36 along with depression
and helplessness in patients with systemic lupus erythematosus.
duration of fatigue is not measured uniformly across all
fatigue instruments; therefore, memory bias could play a
role in the scores of fatigue in the different instruments.
Fourth, medications that may cause fatigue were not assessed in any study. The latter is a limitation that the panel
felt important to be addressed in future studies. The panel
agreed with Dittner et al that there is no gold standard for
fatigue, nor is there ever likely to be (56).
The panel recommended the use of the FSS in clinical
trials and observational studies in SLE patients. The argu-
ments of the panel that led to this recommendation were
that the instrument was developed in patients with SLE, it
is frequently used in SLE studies, and it has valid psychometric properties (including internal consistency, responsiveness, and construct validity. No other instrument met
all these criteria. Furthermore, its availability in several
languages was also considered an advantage suggesting
worldwide acceptance from the scientific community. The
panel further emphasized that the use of a single common
instrument will allow improved efficiency in future re-
Aviña-Zubieta et al
search on fatigue in patients with SLE by enabling results
to be compared across studies and interventions.
Gaps identified by the panel include a closer examination of several dimensions of fatigue in patients with SLE
(severity, impact, trends, affective, and evaluative components), and the identification of factors other than depression, disease activity, sleep quality, and FM. Other important variables such as emotional stressors, environmental
factors, and effect of age, sex, culture, and disease duration
on perception of fatigue need to be addressed. Furthermore, patients’ perspectives on fatigue are critical and
need to be evaluated, especially the ones related to what
they consider the minimal clinically important difference
(MCID; the smallest difference in fatigue score that patients perceive as beneficial and that would mandate a
change in the patient’s management). The MCID will be
essential to interpret the magnitude of longitudinal
changes or differences when comparing therapeutic strategies. This will also be necessary to estimate sample sizes
for future trials using fatigue as an outcome measure.
The panel felt that a recommendation based on experts’
opinion was needed in the absence of evidence; we considered that this was better than nothing at all. Therefore,
we recommended that an important improvement or response could be a 15% decrease in the FSS score. It can be
argued that expert opinion is not a valid approach; however, this strategy has been used as a proxy in the absence
of available information (e.g., to calculate sample sizes).
Furthermore, a recent study from several authors participating in this study evaluated the MCID from the patients’
perspective for several fatigue instruments including the
FSS, and found that a 10% response (95% confidence
interval 4.9 –14.6) will be considered important (58).
In summary, we suggest that in future studies, the FSS is
the best available instrument to measure fatigue in patients
with SLE based on its validated psychometric properties,
the fact that it is the most commonly used instrument to
date, and it has been used and validated in several languages. Future research areas of interest are longitudinal
studies of fatigue in early lupus, identification of clinical
and psychosocial factors as determinants of fatigue in diverse patient populations, and the estimation of the MCID
for fatigue from the patient’s perspective.
Dr. Aviña-Zubieta 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 design. Bischoff-Ferrari, Fischer-Betz, Liang, Phillips,
Schneider, Schur, St.Clair.
Acquisition of data. Aviña-Zubieta, Bischoff-Ferrari, Illei, Liang,
Phillips, Pouchot, St.Clair.
Analysis and interpretation of data. Aviña-Zubieta, Alarcón,
Bischoff-Ferrari, Fischer-Betz, Illei, Liang, Mikdashi, Petri, Phillips, Pouchot, Schneider, Schur, St.Clair.
Manuscript preparation. Aviña-Zubieta, Alarcón, Bischoff-Ferrari, Fischer-Betz, Gall, Liang, Mikdashi, Petri, Phillips, Pouchot,
Schneider, Schur, St.Clair.
Statistical analysis. Aviña-Zubieta, Bischoff-Ferrari, Liang.
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measurements, systematic, lupus, systemic, erythematosus, fatigue, review
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