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Towards a practical management of fatigue in systemic lupus erythematosus



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.
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/
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
© Author(s) (or their
employer(s)) 2020. Re- use
permitted under CC BY- NC. No
commercial re- use. See rights
and permissions. Published by
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).
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
Lupus Science & Medicine
in fatigue scores in a randomised controlled trial in
juvenile- onset SLE.22
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
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
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
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
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
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
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
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.
MertzP, etal. Lupus Science & Medicine 2020;7:e000441. doi:10.1136/lupus-2020-000441
Lupus Science & Medicine
concentrations should be measured to verify therapeutic
adherence and adjust daily posology.56 57
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/.
PhilippeMertz http:// orcid. org/ 0000- 0002- 9781- 7388
LaurentArnaud http:// orcid. org/ 0000- 0002- 8077- 8394
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... Poor sleep, fatigue, and pain are major health problems in patients with systemic lupus erythematosus (SLE) [1] [2]. The prevalence of sleep disorders ranges from 55% to 81% [3], and fatigue is reported in 67% -90% of patients with SLE [4]. ...
... Over 20 types of self-administered questionnaires have been used to measure fatigue [9], but fatigue assessment remains difficult. Pain, medication, disease activity, and mental health are contributors to fatigue [1] [8]. Poor sleep quality, obesity, and reduced physical activity are also included in the risk factors for fatigue [4]. ...
... In nearly half of the participants, fatigue and MVPA duration were major factors associated with sleep duration and cardiopulmonary indicators at night. Physical activity, fatigue, and pain were correlated in less than a quarter of the participants.The correlations between the fatigue levels measured in the evening and poor sleep outcomes are at variance with previous studies on fatigue, which suggest that poor quality of sleep itself is one of the contributory factors to fatigue[1] [4]. However, previous studies using instruments, such as the PSQI and the daily fluctuations in sleep indicators, were not examined. ...
... Pisetsky and colleagues 55 distin guished between manifestations strictly related to SLE disease activity (type 1) such as arthritis, vasculitis, and nephritis, versus those related to damage or non-specific consequences of chronic disease (type 2) including fatigue, myalgia, and depression, which are typically unresponsive to immunosuppressive therapy. [55][56][57][58] Arth ralgia can be difficult to differentiate from inflammatory arthritis and, besides the physician's expertise, the use of advanced imaging might help in the attribution process in doubtful cases. 59 PGA scoring should take into account common clinical laboratory parameters necessary to rate specific organ disease activity (such as urinalysis, serum creatinine level, and blood cell count; statement 1.12) ...
... Review such as fatigue, myalgia, depression, and anxiety are frequently reported by patients as a major source of quality of life impairment. [55][56][57][58][72][73][74] Nevertheless, these symptoms are poorly associated with active SLE and are typically unresponsive to standard immunosuppressive therapy. 55 Avoiding the potential overestimation of PGA scores by considering only findings clearly related to disease activity is therefore an important statement that was agreed upon during the Delphi process. ...
The Physician Global Assessment International Standardisation COnsensus in Systemic Lupus Erythematosus (PISCOS) study aimed to obtain an evidence-based and expert-based consensus standardisation of the Physician Global Assessment (PGA) scoring of disease activity in systemic lupus erythematosus (SLE). An international panel of 79 SLE experts participated in a three-round Delphi consensus process, in which 41 statements related to the PGA in SLE were rated, using a 0 (strongly disagree) to 10 (strongly agree) numerical rating scale. Statements with agreement of 75% or greater were selected and further validated by the expert panel. Consensus was reached on 27 statements, grouped in 14 recommendations, for the use of the PGA in SLE, design of the PGA scale, practical considerations for PGA scoring, and the relationship between PGA values and levels of disease activity. Among these recommendations, the expert panel agreed that the PGA should consist of a 0–3 visual analogue scale for measuring disease activity in patients with SLE in the preceding month. The PGA is intended to rate the overall disease activity, taking into account the severity of active manifestations and clinical laboratory results, but excluding organ damage, serology, and subjective findings unrelated to disease activity. The PGA scale ranges from “no disease activity” (0) to the “most severe disease activity” (3) and incorporates the values 1 and 2 as inner markers to categorise disease activity as mild (≥0·5 to 1), moderate (>1 and ≤2) and severe (>2 to 3). Only experienced physicians can rate the PGA, and it should be preferably scored by the same rater at each visit. The PISCOS results will allow for increased homogeneity and reliability of PGA ratings in routine clinical practice, definitions of remission and low disease activity, and future SLE trials.
... Some studies suggested that sleep disturbances correlate with SLE disease activity and the presence of additional symptoms such as pain and steroid use [6]. Importantly, sleep disturbance symptomatology, such as fatigue and increased pain, overlap with constitutional inflammatory symptoms of SLE and may mimic disease-related relapse [7,8]. ...
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Marked fatigue is common in patients with systemic lupus erythematosus (SLE). This study aimed to assess the association of sleep disorders, including obstructive sleep apnea (OSA), with SLE. Forty-two consecutive patients with SLE and 20 healthy controls were recruited and underwent a one-night ambulatory sleep examination. They completed questionnaires, including the Pittsburgh Sleep Quality Index (PSQI) and Functional Assessment of Chronic Illness Therapy (FACIT). SLE disease activity and damage were assessed by the SLE Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI). A significantly increased apnea/hypopnea index was noted in the SLE group compared to healthy controls (p = 0.004). SLE patients had higher rates of moderate-to-severe OSA (p = 0.04), PSQI (p = 0.001), and FACIT scores (p = 0.0008). Multivariate analysis revealed that the SDI was associated with OSA (p = 0.03). There was a positive association between SLEDAI-2K and moderate-to-severe OSA (p = 0.03). Patients with SLE had an increased prevalence of OSA and poorer quality of sleep compared to healthy controls. Our findings suggest that active disease and accumulated damage may be associated with OSA. These findings highlight the importance of identifying the presence of OSA in patients with SLE.
... Fatigue remains one of the most challenging manifestations reported by patients with SLE. [8][9][10] Fatigue is highly multifactorial and can be related to disease activity, organ damage, psychobehavioural elements or totally independent of the disease itself. [11][12][13] Because of this, it is crucial to determine whether fatigue could be a significant confounder of PGA ratings. ...
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Objectives To analyse whether reported fatigue, one of the most challenging manifestations of systemic lupus erythematosus (SLE), may bias the assessment of disease activity in SLE according to the Physician Global Assessment (PGA). Methods Patients from the Lupus BioBank of the upper Rhein database, a cross-sectional multicentre collection of detailed clinical and biological data from patients with SLE, were included. Patients had to fulfil the 1997 American College of Rheumatology criteria for SLE and the PGA (0–3 scale) at the time of inclusion had to be available. Fatigue was assessed according to the Fatigue Scale for Motor and Cognitive Functions. Univariate and multivariate regression models were built to determine which variables were associated with the PGA. Results A total of 350 patients (89% female; median age: 42 years, IQR: 34–52) were included. The median Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score was 4 (IQR: 2–6). Of these 350 patients, 257 (73%) reported significant fatigue. The PGA (p=0.004) but not the SELENA-SLEDAI (p=0.43) was significantly associated with fatigue. Both fatigue and SELENA-SLEDAI were independently associated with the PGA in two different multivariate models. Conclusion Fatigue is independently associated with disease activity assessed using the PGA but not the SLEDAI. These findings highlight the fact that the PGA should capture only objectively active disease manifestations in order to improve its reliability.
... Goma et al. [18] found that RA affects patients' sex function and in the majority of patients RA affected their sexual lives. Fatigue is also one of the predominant manifestations in patients with RA, [19] and up to 75% of patients experience high levels of fatigue. [20] The researchers found the use of a quantitative approach in previous studies but found no qualitative studies among Iranian patients with RA. ...
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Background: Rheumatoid Arthritis (RA) is a chronic inflammatory disease that affects various systems of the body. The present study was conducted with the aim to explain the lived experiences of Iranian patients with RA. Materials and methods: According to the research question, the phenomenological research approach was used. The participants were selected through purposive sampling, and sampling was continued until data saturation was achieved. The data was collected by conducting unstructured interviews and using an audio recorder. To interpret the data, an interpretive/hermeneutic approach was implemented using Van Manen's method. In addition, Lincoln and Guba's criteria were used to evaluate data robustness. Results: A total of 24 participants participated in the study. Overall, 145 basic concept codes were extracted which were classified into the four main themes of self-management with the participation of the family, spiritual resilience in the face of existing problems, the tendency to hide the disease, and the fear of an uncertain future. Conclusions: It is recommended that care providers use the findings of this study to develop care plans in the various aspects of the physical, mental, social, and spiritual needs of patients with RA based on their concerns and deep experiences. It is also suggested that other qualitative research approach methodologies such as grounded theory for explaining the process of patient care and providing an appropriate model, or action research for solving the problems of hospitalized patients through suitable care at home be implemented.
... Although pharmaceutical interventions dominate lupus control measures, programs using provider strategies or education or reminders for patients can further improve lupus disease control and patient quality of life (18)(19)(20)(21)(22). However, interventional RCTs in mainland China focus on pharmacologic and biologic treatments, while the absence of interventions involving self-management, diet, education, exercise, and care reflects ignorance of the importance of comprehensive management for SLE patients among physicians in mainland China. ...
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Objectives More than a quarter of single-country systemic lupus erythematosus (SLE) interventional randomized clinical trials (RCTs) were conducted in China. To help develop management guidelines and set benchmarks for future SLE research, a systematic review of current trials is needed. Methods We searched systematically three databases and four registries to summarize the interventional RCTs in mainland China and identify factors associated with participant loss. The internal validity of trials was assessed using the Cochrane risk-of-bias tool for assessing risk of bias. The odds ratio (OR) was defined as the ratio of the odds of less than 10% loss to follow-up in the presence or absence of different factors. Results A total of 188 trials met our inclusion criteria, and 15·5% of trials conducted in mainland China ranked low risk of bias. Participant loss was significantly higher among trials that had a defined primary outcome or were registered {primary outcome identification (0·02 [0·00-0·23]) and registration (0·14 [0·03-0·69])}. Trials examining traditional Chinese medicine (TCM) pharmacological treatments had an 8·16-fold (8·16 [1·28-51·98]) higher probability of having low participant loss than trials examining non-TCM pharmacological treatment trials, and trials that did not report masking status had a 15·95-fold (15·95 [2·45-103·88]) higher probability of having low participant loss than open-label trials. In addition, published articles in Chinese also had higher probability of having low participant loss (5·39 [1·10-26·37]). Conclusion SLE trials conducted in mainland China were of relatively poor quality. This situation, including nonrigorous design, lack of registration, and absence of compliance reporting, needs to be ameliorated. To maintain the fundamental repeatability and comparability of mainland China SLE RCTs, transparency of the clinical trial process and complete reporting of the trial data are crucial and urgently needed.
Objective: Fatigue is a prominent and disabling manifestation that impairs the quality of life of Systemic Lupus Erythematosus (SLE) patients both physically and mentally. The majority of SLE patients reports fatigue as an unmet need. Physical exercise could help SLE patients to reduce fatigue and improve quality of life. Methods: A systematic review was conducted to analyse the effectiveness of physical exercise interventions to reduce fatigue in SLE patients. PubMed, EMBASE, Web of Science: Core Collection, the Cochrane Library, CINAHL via EBSCO, and PEDro were searched (March 2021 to October 2021). Studies were included if they fulfilled prespecified criteria and were assessed for quality using the PEDro risk of bias tool. Results: A total of 17 studies (11 RCTs, 3 non-RCTs, 2 one-group pretest-posttest designs, and 1 cross-sectional study) were included in this review. They compared exercise treatment with standard care, alternative treatment, or a different type of exercise. Most of the included studies reported significant improvement in fatigue after exercise therapy. However, study heterogeneity is an important methodological limitation. Exercise interventions did not cause disease flare-ups in patients with low to moderate disease activity. Conclusion: Studies are heterogeneous, precluding firm conclusions. In general, 10 out of 17 studies showed statistically significant but rarely clinically relevant improvement in fatigue after exercise treatment. However, results were not always consistent across different instruments used to assess fatigue. More multi-centred randomised controlled trials are needed to find the best type of physical activity that is both safe and effective for SLE patients.
Rheumatische Krankheiten definieren eine heterogene Krankheitsgruppe mit prominenten Schmerzen des Bewegungsapparats und resultierender Bewegungseinschränkung. Es liegen häufig systemische Autoimmunprozesse zugrunde. Die Prävalenzraten von koexistenten Depressionen und Ängsten sind bei allen rheumatischen Krankheiten signifikant erhöht und je mit negativeren Krankheitsverläufen verbunden. Zumindest für eine rheumatoide Arthritis und einen systemischen Lupus ist empirisch nachgewiesen, dass präexistente affektive und Stress-bezogene Störungen mit einem erhöhten Inzidenzrisiko assoziiert sind. Psychologisch ist der Einfluss von chronischen Schmerzen mit Einschränkungen der allgemeinen Bewegungsfähigkeit prominent. Diese Zusammenhänge müssen auch neurobiologisch reflektiert werden. In den Schmerzzirkel sind Effekte von Angst, Depression und PTBS integral miteinzubeziehen. Lokale pathophysiologische (autoimmune, degenerative, inflammatorische) Prozesse in den Gelenken und angrenzenden Bindegewebsstrukturen gehen über einen Feedbackmechanismus mit einer neuroinflammatorischen Aktivität des ZNS einher. Hierüber werden eine erhöhte affektive und kognitive Vulnerabilität, chronische Müdigkeit, verstärkte Schmerzsensitivität sowie Schlafstörungen induziert. Studien zur Psychotherapie und Pharmakotherapie koexistenter affektiver und Stress-bezogener Symptome bei den diversen rheumatischen Krankheiten werden referiert.
Background: Illness perception has long been hypothesized to be linked to psychological well-b eing in patients with rheumatic diseases, although substantial evidence is lacking, and the contribution of ruminative coping style to this relationship is unclear. Aim: To investigate the roles of illness perception and rumination in predicting fatigue and negative emotions in patients with chronic rheumatic diseases. Methods: Illness perception, rumination, fatigue and negative emotions (i.e. depression, anxiety and stress) were assessed by the Illness Perception Questionnaire-Revised, Stress Reactive Rumination Scale, Multidimensional Assessment of Fatigue, and the Depression, Anxiety and Stress Scale respectively. Multivariate regression analysis, the Sobel test, and the bootstrap were used to identify the mediating effect of rumination. Results: All five subscales of illness perception, including perceived illness identity, chronicity, cyclical nature, consequences and coherence of illness, were significantly associated with fatigue and negative emotions. In mediational analysis, rumination was found to mediate three components of illness perception (the identity, cyclical nature and consequences of illness) and negative emotions/fatigue. Conclusion: Perceived identity, cyclical nature, and consequences of illness are significantly associated with fatigue and negative emotions in patients with chronic rheumatic diseases and these associations are mediated by rumination. Our findings suggest that psychological intervention should target rumination to improve physical and emotional well-being of patients with chronic rheumatic diseases.
Introduction : Most patients with Systemic Lupus Erythematosus (SLE) have limited levels of physical activity (PA). The aim of this systematic review was to examine the evidence regarding the benefits and potential risks of PA in SLE. Methods : We searched the medical literature on MEDLINE (via PubMed) from inception to March 2022 using the Medical Subject Headings (MeSH) terms “Exercise” and “Lupus Erythematosus, Systemic” as well as free text combinations such as “physical activity”. We also searched the reference lists of retrieved studies. Two authors independently assessed all studies identified by the search for inclusion in the review and independently extracted data. Results : A total of 40 articles (2291 SLE patients) published between 1989 and 2022 were included in this systematic review. Compared to the general population, SLE patients had low levels of PA, with 11% to 29.8% objectively meeting World Health Organization (WHO) recommendations. SLE patients also had impaired aerobic capacities (VO2max ranging from 18.8 to 25.78ml/kg/min). Aerobic programs had significant benefits on global aerobic capacity and estimated cardiovascular risk while resistance training programs improved strength and function in SLE. Fatigue, depression and Health-Related Quality of life improved significantly following PA training. No severe adverse event was reported across included studies. Conclusion : Aerobic and resistance training programs had clear benefits and were well tolerated in SLE patients with stable disease. There is currently no universal recommendations about PA in SLE. Dedicated recommendations informed by this systematic review are needed to promote physical activity and its benefits in SLE patients.
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OBJECTIVE: To determine the frequency, associations and outcomes of cerebrovascular events (CerVEs) in a multi-ethnic/racial, prospective, SLE disease inception cohort. METHODS: Patients were assessed annually for 19 neuropsychiatric (NP) events including 5 types of CerVEs: (i) Stroke; (ii) Transient ischemia; (iii) Chronic multifocal ischemia; (iv) Subarachnoid/intracranial hemorrhage; (v) Sinus thrombosis. Global disease activity (SLEDAI-2K), SLICC/ACR damage index (SDI) and SF-36 scores were collected. Time to event, linear and logistic regressions and multi-state models were used as appropriate. RESULTS: Of 1,826 SLE patients, 88.8% were female, 48.8% Caucasian, mean±SD age 35.1±13.3 years, disease duration 5.6±4.2 months and follow-up 6.6±4.1 years. CerVEs were the fourth most frequent NP event: 82/1,826 (4.5%) patients had 109 events, 103/109 (94.5%) were attributed to SLE and 44/109 (40.4%) were identified at enrollment. The predominant events were stroke [60/109 (55.0%)] and transient ischemia [28/109 (25.7%)]. CerVEs were associated with other NP events attributed to SLE (HR (95% CI): (3.16; 1.73-5.75) (p<0.001), non-SLE NP (2.60; 1.49-4.51) (p<0.001), African ancestry at US SLICC sites (2.04; 1.01-4.13) (p=0.047) and organ damage (p=0.041). Lupus anticoagulant increased the risk of first stroke and sinus thrombosis [2.23 (1.11, 4.45) p=.024] and TIA [3.01 (1.15, 7.90) p=0.025]. Physician assessment indicated resolution or improvement in the majority but patients reported sustained reduction in SF-36 summary and subscale scores following CerVEs (P<0.0001). CONCLUSION: CerVEs, the fourth most frequent NP event in SLE, are usually attributable to lupus. In contrast to good physician reported outcomes, patients report a sustained reduction in health-related quality of life following CerVEs. This article is protected by copyright. All rights reserved.
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Background: Systemic Lupus Erythematosus (SLE) is an autoimmune disease which impairs the quality of life. The objective of study was to evaluate the effectiveness of Brief Group Psychoanalytic Psychotherapy to improve quality of life, depression, anxiety and coping strategies in SLE patients. Methods: In a randomized clinical trial, 80 female SLE patients were allocated into two groups: therapy group (n = 37) and control group (n = 43). Therapy group (TG) attended weekly psychotherapy sessions for 20 weeks; control group (CG) remained on a waiting list. Both groups received standard medical care. Questionnaires and scales were applied by blinded evaluators at baseline (T1) and after 20 weeks (T2): Socioeconomic Status, SLE International Collaborating Clinic/American College of Rheumatology-Damage Index, SLE International Disease Activity, SLE Specific Symptom Checklist, SLE Quality of life, Hospital Anxiety Depression Scale, Coping Strategies Inventory. Intent to treat intra- and inter-group analysis was performed for all variables in T1 and T2 using Qui-square, t-Student, Mann-Whitney and Wilcoxon tests. Analysis of Variance was used to compare categorical variables over time. P < 0.05 was considered significant. Results: The mean age of patients was 42 years; 54% were white, with mean disease duration of years 12. At baseline, both groups were homogeneous in all variables, including medications. After 20 weeks of psychotherapy TG was significantly different from CG, with lower frequency of symptoms (p = 0.001), lower level of anxiety (p = 0.019) and depression (p = 0.022), better index in five of six domains of quality of life scale (p ≤ 0.005), including total SLEQOL (p < 0.001) and with higher positive planful problem solving strategy (p = 0.017). No change in disease activity score was observed in both groups. Conclusions: Psychoanalytic psychotherapy was effective to improve many domains of quality of life and one positive coping skill and to reduce SLE symptoms, anxiety and depression levels. Brief group psychotherapy can be a useful tool to complement medical care in SLE patients. Trial registration: Number NCT01840709 .
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From a 1-year survival of less than 50% before the discovery of glucocorticoids to over 90% at 10 years in most dedicated centres, the spectrum of SLE has profoundly evolved. Despite this improvement, several major challenges currently remain. The aim of this review is to analyse what are, according to us, the 10 most important contemporary challenges in the management of SLE. Among those are the need to treat to target to favour disease remission (or low disease activity), limit the use of glucocorticoids, derive more comprehensive tools for the evaluation of disease activity, develop more effective drugs (yielding successful trials), dissect the heterogeneity of the disease both at the molecular and genetic levels, identify relevant biomarkers for individualised treatment, manage fertility and pregnancy, tackle comorbidities such as cardiovascular risk, the prevention of infections and osteoporosis, improve the network of care (from the patients’ perspective), and favour a holistic approach (integrating fatigue, adherence to treatment, physical activity). Altogether, these 10 contemporary challenges in SLE may be considered as a roadmap for those involved in the daily care of patients with SLE, as well as for researchers who may wish to contribute to an improved management of this rare and complex disease.
Objective The prevalence of fatigue is high in patients with systemic lupus erythematosus (SLE). In this study, we used latent class analysis to reveal patterns of fatigue, anxiety, depression and organ involvement in a large international cohort of SLE patients. Methods We used the Lupus BioBank of the upper Rhein to analyse patterns of fatigue using latent class analysis (LCA). After determining the optimal number of latent classes, patients were assigned according to model generated probabilities, and characteristics of classes were compared. Results A total of 502 patients were included. Significant fatigue, anxiety and depression were reported by 341 (67.9%), 159 (31.7%) and 52 (10.4%) patients, respectively. LCA revealed a first cluster (67.5% of patients) with low disease activity [median (25th–75th percentile interquartile range) Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI: 2 (0–4)], significant fatigue (55.5%, P < 0.0001), low anxiety (11.8%, P < 0.0001) and depression (0.9%, P < 0.0001). Cluster 2 (25.3%) also comprised patients with low disease activity [SELENA-SLEDAI: 2 (0–6)], but those patients had a very high prevalence of fatigue (100%, P < 0.0001), anxiety (89%, P < 0.0001) and depression (38.6%, P < 0.0001). Cluster 3 (7.2%) comprised patients with high disease activity [SELENA-SLEDAI: 12 (8–17), P < 0.0001] and high fatigue (72.2%, P < 0.0001) with low levels of anxiety (16.7%, P < 0.0001) and no depression (0%, P < 0.0001). Conclusion LCA revealed three patterns of fatigue with important practical implications. Based on these, it is crucial to distinguish patients with active disease (in whom remission will be achieved) from those with no or mild activity but high levels of fatigue, depression and anxiety, for whom psychological counselling should be prioritized.
Background: Fatigue, although common and associated with outcomes in dialysis-dependent chronic kidney disease (CKD), has not been studied in nondialysis chronic kidney disease (CKD-ND) patients. Methods: In this longitudinal cohort of 266 outpatients with CKD-ND stages 2-5, we measured self-reported fatigue on 3 scales-Quick Inventory of Depression Symptomatology-Self Report (QIDS-SR16), Beck Depression Inventory-I (BDI-I), and short form 12 health survey (SF-12) questionnaires and evaluated the prespecified composite of progression to dialysis initiation, death, or hospitalization after 12 months. Logistic and linear regression assessed characteristics associated with fatigue. Survival analysis measured associations of fatigue with outcomes. Results: Mean age was 64.4 ± 12.0 years, and mean estimated glomerular filtration rate (eGFR) was 31.6 ± 16.7 mL/min/1.73 m2. Fatigue was common, with 69.2% reporting fatigue on QIDS-SR16 and 77.7% on BDI-I. Unemployment, comorbidities, use of antidepressant medications, and lower hemoglobin correlated with fatigue. There were 126 outcome events. Participants that reported any versus no fatigue on QIDS-SR16 were more likely to reach the composite, hazard ratio (HR) 1.70 (95% CI 1.11-2.59), which persisted after adjusting for demographics, comorbidities, substance abuse, hemoglobin, albumin, eGFR, and calcium-phosphorus product, HR 1.63 (1.05-2.55). Fatigue severity by the SF-12 was also associated with outcomes independent of demographics, comorbidities, and substance abuse, HR per unit increase 1.18 (1.03-1.35). No association was observed with fatigue on the BDI-I. Conclusion: Fatigue affected about 2/3 of CKD-ND patients and associated with unemployment, comorbidities, antidepressant medication use, and anemia. Fatigue measured by the QIDS-SR16 and SF-12 independently predicted outcomes in CKD patients. Eliciting the presence of fatigue may be a clinically significant prognostic assessment in CKD patients.
Objectives To quantify changes in generic patient-reported outcomes against clinically meaningful, disease activity measures in systemic lupus erythematosus (SLE). Methods Using BLISS-52 trial data (867 SLE patients), we estimated the mean difference in change of patient-reported outcome scores (Medical Outcomes Study SF-36 and FACIT-fatigue) in relation to disease activity (SELENA-SLEDAI, SELENA-SLEDAI flare index, SLE responder index and British Isles Lupus Assessment Group (BILAG)), considering all study visits by the mean of multivariate mixed models. Predefined disease activity criteria were used to define for improvement and worsening. Results Mean changes in physical component summary/mental component summary and FACIT-fatigue in response to changes in SELENA-SLEDAI and SELENA-SLEDAI flare index were significantly lower than 2.5. New SELENA-SLEDAI flare index flare led to a significant change in all patient-reported outcome scores, except role emotional. Mean improvement in patient-reported outcomes with achievement of SLE responder index ranged between +6.2 (physical function) and +11.3 (bodily pain) for SF-36 domains, + 3.4 and +3.3 for mental component summary and physical component summary, and was +4.2 for FACIT-fatigue. When considering disease activity changes by organ system, changes in BILAG (constitutional) was independently associated with significant changes in FACIT-fatigue and all SF-36 domains (except physical function), changes in BILAG (musculoskeletal and hematological) were independently associated with significant changes in patient-reported outcome scores, except for role emotional (musculoskeletal) and general health/mental health (hematological). Mean changes in every SF-36 domain varied (and was >5) with SLE responder index attainment. Conclusions Knowledge of changes in patient-reported outcomes, against clinically meaningful changes in SLE disease activity measures, is crucial for designing of clinical trials, interpretation of results and shared decision-making for patient care.
Systemic lupus erythematosus (SLE) is a complex disease with variable presentations, course and prognosis. Published studies present conflicting data regarding the impact of cigarette smoking on SLE risk, disease activity, clinical manifestations and treatment response. We performed a comprehensive literature search using Medline, EMBASE and the Cochrane Collaboration database, and hand searches of relevant bibliographies. All original studies investigating the relationship between smoking and SLE were included in TABALUP. Two investigators systematically extracted data from the relevant studies. When possible, meta-analyses were performed. The meta-analysis of 9 case-controls studies show an increased risk of SLE in current-smokers compared to never-smokers (OR: 1.49 [95%CI: 1.06-2.08]), while former-smokers were not at increased risk of SLE. Data on passive smoking remains scarce and controversial. Pooled analysis studies did not find an over-risk of anti-dsDNA, anti-Sm or anti-SSA positivity according to smoking status. Tobacco smoking significantly reduced the therapeutic effectiveness of hydroxychloroquine in cutaneous lesions (pooled OR 0.53; 95%CI: 0.305-0.927) and belimumab in systemic manifestations (HR 0.10; 95% CI 0.02-0.43). In addition to its usual adverse effects, cigarette smoking is a risk factor of SLE and negatively influences the course of the disease and its treatment. We believe that smoking cessation should be one of the main target of physicians treating SLE patients.
OBJECTIVES: Fatigue remains a debilitating feature of systemic lupus erythematosus (SLE). Although in some cases this may be the result of intercurrent fibromyalgia, mood disorder or untreated metabolic syndrome, in many cases the cause is unclear. The aim of this study was to investigate the relationship between fatigue and red cell distribution width (RDW), a measure of variability in erythrocyte size and volume. METHODS: A total of 225 patients were recruited from three clinics in England and Australia. Patients completed the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score or 12-item Short Form survey (SF-12) to measure fatigue, which was compared with RDW and haemoglobin. In a subgroup of 72 patients, markers of disease activity were also assessed for correlation with fatigue using univariate and multivariate analysis with fatigue as the dependent variable. RESULTS: In all three groups, significant correlations between fatigue and RDW were observed (p<0.001; p=0.02; p<0.001 respectively) and this was preserved in multivariate analysis. There was no correlation between fatigue and haemoglobin in two groups (with the correlation between RDW and fatigue remaining significant in non-anaemic patients in the third group). In subgroup analysis, fatigue was not associated with any measures of disease activity. CONCLUSIONS: We report a reproducible, statistically significant association between RDW and fatigue levels in a diverse population of patients with SLE. The findings of this study raise the possibility of a potential novel biological basis for fatigue in those in whom there is a lack of an alternate explanation.
Background: Non-pharmacologic therapies have been deemed as potentially beneficial for patients with systemic lupus erythematosus. We conducted an updated review to determine the effects of these therapies to inform practice. Methods: A literature search was performed using PubMed (MEDLINE), EMBASE, Cochrane, PsychINFO, the Cumulative Index to Nursing and Allied Health Literature, Web of Science, and Google Scholar from inception until August 2018. We included randomized controlled trials of non-pharmacologic therapies in systemic lupus erythematosus patients with sample size ≥10. Systemic lupus erythematosus was defined by 1982 or 1997 American College of Rheumatology criteria. Studies were synthesized separately by patient-reported outcomes and disease activity. Due to the heterogeneity of interventions and comparisons, a meta-analysis was not performed. Results: A total of 15 randomized controlled trials involving 846 participants met the inclusion criteria. Of the 15 trials, eight used exercise interventions, six used psychological interventions (one group psychotherapy, three cognitive behavioral therapies, one psychoeducation, one mindfulness-based cognitive therapy) and one used electro-acupuncture. Five of 15 studies utilized control groups consisting of usual medical care. Other studies included control interventions of relaxation, attention placebo, symptom monitoring support, education, minimal needling, isotonic and resistance exercise. Compared with the control conditions, non-pharmacological interventions were associated with a significant improvement in fatigue in three out of six studies. Three out of eight studies reported improved anxiety and depression, and one study reported improved pain after interventions. Seven out of 11 studies reported improvement in overall quality of life in at least one domain of the Short-Form Health Survey. Of note, no studies demonstrated an improvement in disease activity after 5-52 weeks of non-pharmacological therapies. Conclusion: This review showed promising results for physical exercise and psychological interventions as adjuncts to traditional medical therapy for improvement in fatigue, depression, pain and quality of life for systemic lupus erythematosus. Further high-quality randomized controlled trials with longer follow-up periods are warranted.
Objective Fatigue is reported in up to 90% of patients with SLE. This study was conducted to identify the determinants associated with fatigue in a large cohort of patients with SLE, as well as to provide a systematic review of the literature. Methods Patients from the Lupus BioBank of the upper Rhein, a large German–French cohort of SLE patients, were included in the FATILUP study if they fulfilled the 1997 ACR criteria for SLE and had Fatigue Scale for Motor and Cognitive Functions scores collected. Multivariate logistic regression analyses were performed to assess the determinants of fatigue and severe fatigue. Results A total of 570 patients were included (89.1% female). The median age was 42 years (interquartile range 25–75: 34–52). The median value of the SAfety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI was 2 (0–4). Fatigue was reported by 386 patients (67.7%) and severe fatigue by 209 (36.7%). In multivariate analyses, fatigue was associated with depression [odds ratio (OR): 4.72 (95% CI: 1.39–16.05), P = 0.01], anxiety [OR: 4.49 (95% CI: 2.60–7.77), P < 0.0001], glucocorticoid treatment [OR: 1.59 (95% CI 1.05–2.41), P = 0.04], SELENA-SLEDAI scores [OR: 1.05 (95% CI: 1.00–1.12) per 1 point increase, P = 0.043] and age at sampling [OR: 1.01 (95% CI: 1.00–1.03) per 1 year increase, P = 0.03]. Severe fatigue was independently associated with anxiety (P < 0.0001), depression (P < 0.0001), glucocorticoid treatment (P = 0.047) and age at sampling (P = 0.03). Conclusion Both fatigue and severe fatigue are common symptoms in SLE, and are strongly associated with depression and anxiety. Disease activity and the use of glucocorticoids were also independently associated with fatigue, although more weakly.