Fatigue in Patients With Systemic Lupus Erythematosus Linked to Anxiety and Depression


While some patients with systemic lupus erythematosus (SLE) find it beneficial to receive anti-inflammatory therapy to treat their fatigue, there is increasingly more evidence that chronic diseases increase risk of psychiatric disorders, such as anxiety and depression, which need to be treated differently.

Patients with neuropsychiatric systemic lupus erythematosus (NPSLE) may need intervention strategies that focus on anxiety and depression rather than immunosuppressive treatment in order to treat unexplained fatigue, according to a study published in SAGE Journals1.

Fatigue is incredibly common in patients with systemic lupus erythematosus (SLE), with up to 90% reporting the symptom. Unfortunately, a clear treatment strategy has been elusive. While some patients find it beneficial to receive anti-inflammatory therapy, there is increasingly more evidence that chronic diseases increase risk of psychiatric disorders, such as anxiety and depression. These disorders may need to be treated through other measures, such as psychotherapy and exercise, which both reduce fatigue and depressive symptoms as well as improve cognition for patients with SLE.

“Based on previous research, the relationship between inflammation and fatigue in patients with SLE remains unclear,” explained investigators. “This is the first study to compare fatigue in SLE patients with inflammatory vs. non-inflammatory neuropsychiatric symptoms, and inflammation of the nervous system did not increase the presence or severity of fatigue.”

The study, which ran from 2007-2019, examined patients who visited the NPSLE clinic of the Leiden University Medical Center (LUMC). Investigators studied potential risk factors, including stress, inflammation, and neuropsychiatric events, to discover reasons for patient fatigue. A multidisciplinary consensus meeting classified neuropsychiatric symptoms of inflammatory origin (inflammatory phenotype) or other origin (non-inflammatory phenotype). Additionally, patients underwent laboratory investigation and a brain MRI in order to assess the presence of NPSLE. Data was collected on demographics, clinical presentation, SLE and NPSLE diagnosis, and medication usage.

Investigators measured levels of anxiety and depression using the Hospital Anxiety and Depression Scale (HADS), which consisted of an anxiety symptoms score (HADS-A, range 0-21) and a depression symptoms score (HADS-D, range 0-21). Patients with scores ≤ 7 were not considered to have anxiety or depression, scores between 8-10 indicated a possibility of disorder, and scores ≥ 11 reflected probable disorder.

The Dutch version of the Short-Form 30 vitality domain (SF-36 VT) assessed fatigue at a patient’s first visit to the NPSLE clinic. Questions were evaluated on a 6-point scale, ranging from “none of the time” to “all of the time” and results ranged from 0-100. From 2011 onwards, the Multidimensional Fatigue Inventory (MFI) and Visual Analogue Scale (VAS) were also used to measure fatigue. The MFI consisted of 20 questions rated on a 5-point scale, with answers ranging from “yes, that is true” to “no, that is not true.” Scores were categorized into subscales: general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. Total scores ranged from 20-100. VAS asked the question, “How tired were you this past week?” on an 11-point scale from 0 (“not tired”) to 10 (“extremely tired”).

Inflammatory neuropsychiatric symptoms and fatigue were evaluated using separate analyses of the 3 assessment tools in multiple regression analyses (MRA). MRA also studied any possible associate between anxiety and depression, according to the HADS scores and fatigue assessment tools. Afterwards, results were further adjusted for age, sex, and education.

Of the 371 patients who were eligible, 348 (94%) were able to take the questionnaires. Of these 348, 72 patients had neuropsychiatric symptoms of an inflammatory origin (21%). The mean age for inflammatory and non-inflammatory patients was 42 ± 14 and 44 ± 13 years, respectively, and 87% were female.

Fatigue was defined as ≥1 standard deviation (SD) away of the mean of age-related controls (the general population) on the SF-36 VT and was present in 78% of patients with both inflammatory and non-inflammatory phenotypes. Extreme fatigue, defined as ≥2 SD away, was present in 50% of inflammatory patients and 46% of non-inflammatory phenotypes. There was no association between disease activity and fatigue.

Investigators did, however, discover a strong correlation between both anxiety and depressive symptoms and fatigue. Patients with no, possible, and probable depression exhibited fatigue 61%, 90%, and 96%, respectively.

The HADS assessment found a high percentage of anxiety and depression symptoms, with one-third of all patients in the ≥11 range on the subscales. As symptoms of anxiety and depression have been strongly associated with fatigue, investigators believe that physicians addressing these symptoms may not only decrease fatigue but improve a patient’s quality of life.

The well-defined patient population was a clear strength of the study, as well as the variety of tools used to measure fatigue, anxiety, and depression, all of which showed no correlation between inflammation and fatigue. However, the observational nature of the study can be seen as a limitation. Further, additional aspects that may affect fatigue were not studied.

“We demonstrated that patients with SLE and neuropsychiatric symptoms are extremely fatigued, independent of underlying etiology (inflammatory vs. non-inflammatory) of these symptoms and disease activity,” investigators concluded. “As fatigue is strongly associated with anxiety and/or depressive symptoms, targeting mood (disorders) may be an appropriate treatment strategy.”


Monahan RC, Beaart-van de Voorde LJ, Eikenboom J, et al. Fatigue in patients with systemic lupus erythematosus and neuropsychiatric symptoms is associated with anxiety and depression rather than inflammatory disease activity [published online ahead of print, 2021 Mar 28]. Lupus. 2021;9612033211005014. doi:10.1177/09612033211005014

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