Towards a practical management of fatigue in systemic lupus erythematosus

Abstract

Significant fatigue is reported by two-thirds of patients with SLE and severe fatigue by one-third. The assessment and treatment of fatigue remains a major challenge in SLE, especially in patients with no disease activity. Here, we suggest a practical algorithm for the management of fatigue in SLE. First, common but non–SLE-related causes of fatigue should be ruled out based on medical history, clinical and laboratory examinations. Then, presence of SLE-related disease activity or organ damage should be assessed. In patients with active disease, remission is the most appropriate therapeutic target while symptomatic support is needed in case of damage. Both anxiety and depression are major independent predictors of fatigue in SLE and require dedicated assessment and care with psychological counselling and pharmacological intervention if needed. This practical algorithm will help in improving the management of one the most common and complex patient complaints in SLE.

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MertzP, etal. Lupus Science & Medicine 2020;7:e000441. doi:10.1136/lupus-2020-000441
Towards a practical management of
fatigue in systemic lupus erythematosus
Philippe Mertz ,1,2 Aurélien Schlencker,1,2 Matthias Schneider,3
Pierre- Edouard Gavand,2,4 Thierry Martin,2,4 Laurent Arnaud 1,2
To cite: MertzP, SchlenckerA,
SchneiderM, etal. Towards
a practical management
of fatigue in systemic
lupus erythematosus.
Lupus Science & Medicine
2020;7:e000441. doi:10.1136/
lupus-2020-000441
Received 25 August 2020
Revised 22 October 2020
Accepted 30 October 2020
1Department of Rheumatology,
Hôpitaux universitaires de
Strasbourg, Strasbourg, France
2Centre National de Référence
des Maladies Systémiques
et Auto- immunes Rares Est
Sud- Ouest (RESO), Strasbourg,
France, France
3Policlinic for Rheumatology
& Hiller Research Centre for
Rheumatology, Heinrich- Heine-
University, Düsseldorf, Germany
4Service d'immunologie clinique,
Hopitaux universitaires de
Strasbourg, Strasbourg, France
Correspondence to
Pr Laurent Arnaud; laurent.
arnaud@ chru- strasbourg. fr
Review
© Author(s) (or their
employer(s)) 2020. Re- use
permitted under CC BY- NC. No
commercial re- use. See rights
and permissions. Published by
BMJ.
ABSTRACT
Signicant fatigue is reported by two- thirds of patients
with SLE and severe fatigue by one- third. The assessment
and treatment of fatigue remains a major challenge in
SLE, especially in patients with no disease activity. Here,
we suggest a practical algorithm for the management of
fatigue in SLE. First, common but non–SLE- related causes
of fatigue should be ruled out based on medical history,
clinical and laboratory examinations. Then, presence of
SLE- related disease activity or organ damage should be
assessed. In patients with active disease, remission is the
most appropriate therapeutic target while symptomatic
support is needed in case of damage. Both anxiety and
depression are major independent predictors of fatigue
in SLE and require dedicated assessment and care with
psychological counselling and pharmacological intervention
if needed. This practical algorithm will help in improving
the management of one the most common and complex
patient complaints in SLE.
SLE is a chronic autoimmune disease which
may cause a broad spectrum of clinical mani-
festations as well as subjective symptoms1 2
such as fatigue. In SLE, fatigue is reported
by 67% to 90% of patients1 3 4 and is rated
as severe in up to one- third of patients using
validated fatigue instruments, as shown in
the recent multicentre FATILUP study.1
Also, fatigue is often reported as the most
debilitating symptom of the disease by
patients5 6 and leads to both altered health-
related quality of life4 7–9 and significant work
disability with tremendous indirect costs.3
The rational assessment and treatment of
fatigue remains a major challenge in SLE,5
especially in patients without active disease.
Noteworthy, fatigue is a highly multifactorial
concept10 which, in the context of SLE, may
be due either to lupus- related or non–lupus-
related general causes. Importantly, those
causes can also be intricate with significant
psychobehavioural determinants. Here, we
suggest a practical step- by- step algorithm for
the general assessment and management of
fatigue in SLE (figure 1).
STEP 1: SEARCH FOR A GENERAL (NON–LUPUS-
RELATED) CAUSE OF FATIGUE
In the primary care setting, a medical or
psychiatric diagnosis can be found in at least
two- thirds of patients presenting with acute
fatigue. The most frequent causes of fatigue
are summarised in table 1. It is crucial to
understand the patient’s perspective, the
detailed history of fatigue and the impact on
the patient’s mood as well as on daily activi-
ties such as work, household chores, physical
activity and leisure. Box 1 summarises the
main questions to be asked when confronted
with a patient with fatigue. A review of current
medications is suggested, as some drugs may
induce fatigue (eg, antihypertensive drugs
such as beta blockers or sedatives). Lifestyle
assessment is also essential: a significant asso-
ciation between smoking and fatigue has
been reported in SLE.11–14 Also, obesity has
been associated with increased fatigue both
in the general population and SLE.15
A full clinical examination of the heart,
lung, thyroid and nervous system16 is crucial.
For women, a gynaecological examination
is also recommended, especially in case of
anaemia.17 18 Laboratory tests should rule out
most common causes of fatigue (box 1) such
as inflammation and infection, anaemia,
renal or hepatic failure, viral hepatitis or HIV
infection, and major endocrine or metabolic
complications such as abnormal calcemia,
hypothyroidism, diabetes or adrenal insuf-
ficiency (especially in patients who recently
stopped glucocorticoids). Cancer screening
should be updated, according to current
guidelines, and indirect signs of malignancy
(anorexia, weight loss and lymphadenopathy)
should be carefully searched for. Although
controversial,19 vitamin D deficiency has
been associated with fatigue in SLE.20 In an
observational study of 80 patients with SLE,
vitamin D supplementation improved fatigue
in participants.21 Also, vitamin D supple-
mentation was associated with a decrease

MertzP, etal. Lupus Science & Medicine 2020;7:e000441. doi:10.1136/lupus-2020-000441
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in fatigue scores in a randomised controlled trial in
juvenile- onset SLE.22
STEP 2: OBJECTIVE ASSESSMENT OF FATIGUE USING
VALIDATED PROS
Because fatigue is a highly subjective symptom, the stand-
ardised assessment of fatigue using validated patient-
reported outcomes (PROs) is an important step. The use
of validated PROs also allows for an individual follow- up
of fatigue intensity and symptoms over time, and may help
in underlining the benefit of a therapeutic intervention at
the patient level. It is also a way to show that the physician
is genuinely interested in understanding and treating the
cause of fatigue, which is important from the patient’s
perspective, and helps in establishing a trusting physi-
cian–patient relationship. Among a total of 16 different
fatigue PROs which have been used in SLE, the FSS
(Fatigue Severity Scale) and the short- FSS are the most
used ones, but the MFI (Multi- dimensional Fatigue Inven-
tory) and the Fatigue- VAS have also been used, although
less commonly16 (see table 2). The FACIT- Fatigue score is
commonly used in clinical trials but has been infrequently
used in routine clinical practice.1
STEP 3: IDENTIFYING A LUPUS-RELATED CAUSE OF FATIGUE
Fatigue can be a manifestation of active SLE but can also
be related to organ damage (figure 2). The relationship
between disease activity and fatigue remains controversial
in SLE and has been shown to be less strong than with
other factors such as anxiety or depression.1 23 24 Its asso-
ciation with serological markers (C3, anti- dsDNA anti-
bodies) is also controversial.11
Fatigue has been associated with several SLE- specific
organ manifestations:
►Several studies found an association between neuro-
logical involvement,11 25 including white matter hyper-
intensities,26 and fatigue.
Figure 1 Practical algorithm for the management of fatigue
in patients with SLE.
Table 1 Frequent causes of fatigue and suggested rst- line assessment
Common causes of fatigue First- line assessment
Drug- induced fatigue Steroids, anti- arrhythmic, anti- hypertensive,
benzodiazepines or other antidepressant and sedative
agents, anti- histaminic, diuretics
Medication review
Pregnancy β-HCG
Anaemia Iron or vitamin deciencies C- reactive protein, haemoglobin,
Coombs test, ferritin, B9 and B12 vitamins
Metabolic disorders Hypothyroidism, adrenal insufciency, panhypopituitarism TSH, fasting glucose…
Vitamin D insufciency Vitamin D levels
Infection Chronic bacterial (mycobacterial) or viral (HIV, hepatitis B
and C, EBV) infections
C reactive protein
Hepatitis B/C, EBV and HIV serology
Quantiferon
Organ failure Cardiac insufciency
Respiratory insufciency
Liver insufciency
Kidney insufciency
BNP, chest X- ray, echocardiography
creatinine, full hepatic tests
Sleep disorders Obstructive sleep apnoea syndrome
Jet lag syndrome in frequent travellers
Polysomnography
b- HCG, b- human chorionic gonadotropin hormone; BNP, brain natriuretic peptide; EBV, Epstein- Barr virus; TSH, thyroid- stimulating hormone.
Box 1 Checklist for the initial assessment of fatigue in
SLE
1. Characterisation of fatigue:
– Onset: acute or insidious
– Evolution: recent (<1 month), persistent (<6 months) or chronic
(>6 months)
– Presence of fatigue- free periods
– Is fatigue ameliorated by rest?
– Physical and mental impact of fatigue
2. Assessment of lifestyle (work, restrictive diet or obesity, physical
activity), habitus (smoking, drinking) and sleep quality
3. Presence of concurrent manifestations
– Lupus are?
– Any other (non–SLE- related) disorder?
4. List of medications
5. List of previous or current associated medical conditions

MertzP, etal. Lupus Science & Medicine 2020;7:e000441. doi:10.1136/lupus-2020-000441 3
Review
►Renal failure can be an important cause of fatigue. It
is crucial to assess whether it is related to active kidney
disease or to chronic lesions (damage).27 28
►Cardiac failure is an obvious cause of fatigue.
►Hepatic failure and cirrhosis can (rarely) be due to
lupus hepatitis, and overlap with autoimmune hepa-
titis or less frequently sclerosing cholangitis.29 30
Other clinical manifestations of SLE have been asso-
ciated with fatigue: in the FATILUP study,1 we found
arthritis and oral ulcers to be individual SLE Disease
Activity Index score components associated with severe
fatigue. This may underline a more specific role for
painful disease manifestations in SLE.11 23
Finally, the prevalence of fibromyalgia is estimated to
range between 6.2% and 22% of patients with SLE31 32
and has been strongly associated with fatigue.33 Sjögren’s
syndrome should also be thought of in patients with sicca
syndrome and has been associated with significant fatigue
across several studies.34 35
STEP 4: LOOKING FOR INTRICATE PSYCHOLOGICAL
DETERMINANTS
Emotional and functional well- beings as well as abnormal
illness- related behaviours strongly correlate with depres-
sion and fatigue in SLE.1 36 37 Pain, stress and depression
have been shown to be the most important predictors
of fatigue in patients with SLE38 and their intensity and
consequences should be assessed, with the help of a
psychologist or psychiatrist if needed. Mood disorders are
reported in up to 13% of patients with SLE and attributed
to SLE in about 40% of cases.39 Sleep disorders are also
common in the general population as well as in SLE, and
have been associated with fatigue40–42 and depression.41
TOWARDS A PRACTICAL MANAGEMENT OF FATIGUE IN
PATIENTS WITH SLE
In patients with significant disease activity, the main ther-
apeutic target is remission (or alternatively low- disease
activity) and reaching these goals can be sufficient to
improve fatigue.43 44 However, a common situation is the
presence of significant fatigue contrasting with the absence
of disease activity or any underlying organic cause. In
these patients, immunosuppressive treatment escalation
is not indicated and other non- pharmacological interven-
tions such as psychological and behavioural assessment or
physical activity workshops should be favoured.45 Impor-
tantly, lack of optimal physical activity as well as sedentary
behaviour have been associated with fatigue in SLE.44 46 47
Physical exercise is recommended for the management
of pain and fatigue in patients with inflammatory arthritis
in the last European League Against Rheumatism recom-
mendations.48 Physical activity has been shown to improve
fatigue in patients with SLE,44 49 with more time spent in
moderate or high physical activity associated with less
fatigue.50 Patients with SLE with otherwise unexplained
fatigue should undergo dedicated psychological assess-
ment, and behavioural issues should be specifically taken
care of using appropriate psychological counselling51–55
and pharmacological intervention, when needed. The
exact benefit of antidepressants on fatigue is difficult to
assess in SLE because there is no specific trial, but there
is no reason to believe that those treatments would not
be appropriate, keeping in mind the potential interaction
with hydroxychloroquine, which may lead to QT prolon-
gation. Tobacco smoking cessation should be encouraged
as it significantly reduces therapeutic efficacy of many
drugs and could promote flares.14 Last but not least,
hydroxychloroquine observance should be evaluated and
if needed, non- scheduled hydroxychloroquine serum
Table 2 Most frequently used fatigue patient- reported outcomes (PROs) in SLE
Fatigue PROs Description
Fatigue Severity Scale (FSS) 9- item scale covering the general aspects of fatigue
Originally derived for people with multiple sclerosis and SLE
Multi- dimensional Fatigue Inventory (MFI) 20- item scale divided into ve domains: general fatigue, physical fatigue, mental
fatigue, reduced motivation and reduced activity
The threshold for signicant fatigue depends on age and gender
Visual analogue scale to evaluate fatigue
severity (VAS- F)
The scale consists of 18 items related to the subjective experience of fatigue, using
fatigue and energy subscales
Functional Assessment of Chronic Illness
Therapy–Fatigue (FACIT- Fatigue)
13- item self- reported questionnaire assessing aspects of physical and mental
fatigue, and their effects on function and daily living
Figure 2 Main determinants of fatigue in patients with SLE.

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concentrations should be measured to verify therapeutic
adherence and adjust daily posology.56 57
CONCLUSION
Significant fatigue is reported by two- thirds of patients
with SLE and severe fatigue by one- third.1 As in the
general population, general non–SLE- related causes
of fatigue should be ruled out. Then, it is important to
assess whether fatigue may be related to disease activity or
damage. In the former situation, disease remission is the
most appropriate therapeutic target, with an emphasis
on painful manifestations. Importantly, both anxiety and
depression are major independent predictors of fatigue
in several studies. These manifestations should be thor-
oughly assessed and taken care of using appropriate
psychological counselling and pharmacological interven-
tion, when needed. We believe this practical algorithm
will help in improving the management of one of the
most common and complex patient complaints in SLE.
Twitter Laurent Arnaud @Lupusreference
Contributors All authors have equally contributed to this work.
Funding The authors have not declared a specic grant for this research from any
funding agency in the public, commercial or not- for- prot sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in
the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No additional data are available.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY- NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non- commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non- commercial. See:http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.
ORCID iDs
PhilippeMertz http:// orcid. org/ 0000- 0002- 9781- 7388
LaurentArnaud http:// orcid. org/ 0000- 0002- 8077- 8394
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