Fatigue May Artificially Increase Disease Activity Scores in Lupus

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Fatigue, a highly multifactorial manifestation of lupus, can be related to disease activity or independent of the disease itself. Investigators determined whether fatigue could be a significant confounder of Physician Global Assessment ratings.

Fatigue, a common and challenging manifestation of lupus, was associated with disease activity according to the Physician Global Assessment (PGA) but not the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Therefore, when evaluating systemic lupus erythematosus (SLE), the PGA should only capture objectively active disease manifestations to improve reliability, according to a study published in Rheumatic and Musculoskeletal Diseases.1

“The current definitions of remission and low disease activity in SLE incorporate the PGA,” investigators explained. “In a recent systematic review by our group, the PGA was found to be a valid, responsive, and feasible instrument. However, the PGA has high variability due to a lack of standardization in its rating… Fatigue is highly multifactorial and can be related to disease activity, organ damage, psychobehavioral elements, or totally independent of the disease itself. Because of this, it is crucial to determine whether fatigue could be a significant confounder of PGA ratings.”

Patients from the Lupus BioBank of the upper Rhein (LBBR) database were included in the study. Eligible patients fulfilled ≥4 of the 1997 American College of Rheumatology (ACR) criteria for SLE and PGA information was available at the time of inclusion. Fatigue was measured using the Fatigue Scale for Motor and Cognitive Functions (FSMC), a self-reported questionnaire. Depression and anxiety were determined via the Hospital Anxiety and Depression Scale (HADS). Both univariate and multivariate regression models evaluated which variables were linked with the PGA.

Of the 350 patients enrolled in the study, 312 were female (89%) with a median age of 42 years. Participants had a median Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score of 4 (Interquartile range [IQR]: 2–6).

Fatigue was reported in 73% (n = 257) of patients, including 219 (63%) patients with cognitive fatigue, 246 (70%) with motor fatigue, and 144 (41%) with severe fatigue. Of the patients experiencing fatigue, incidences of anxiety (n = 97, 42%) and depression (n = 34, 15%) were significantly higher when compared with those without fatigue (p<0.0001 and p=0.002, respectively).

No significant differences were noted in the median SELENA-SLEDAI score between patients with and without fatigue. However, the PGA was higher (p=0.004) in those reporting fatigue (median: 0.5, IQR: 0.2–1) when compared with patients without fatigue (median: 0.3, IQR: 0.2–0.95). Results remained significant after adjusting for disease activity according to SELENDA-SLEDAI score (p=0.01). According to 2 different multivariate models, fatigue and SELENA-SLEDAI were independently associated with the PGA.

Fatigue ratings, collected as categorical data according to validated thresholds, may have impacted statistical modulation. However, the large number of cases in the database counteracted this limitation. Further, fatigue is a subjective manifestation and none of the routine fatigue evaluation scores have been developed for or validated in SLE. Lastly, investigators underline that results should be interpreted in terms of the patients’ current treatment plans, which may explain the low median SELENA-SLEDAI scores.

“Altogether, our findings highlight the importance of taking into account only objectively active (type 1) manifestations when assessing the PGA in SLE,” investigators concluded. “Doing this may avoid harmful and inappropriate treatment escalation and improve the standardization of the PGA when assessing remission or lupus low disease activity state.”


Mertz P, Piga M, Chessa E, et al. Fatigue is independently associated with disease activity assessed using the Physician Global Assessment but not the SLEDAI in patients with systemic lupus erythematosus. RMD Open. 2022;8(2):e002395. doi:10.1136/rmdopen-2022-002395