Objective Fatigue is a common symptom in systemic lupus erythematosus (SLE), and engaging in physical activity (PA) may reduce fatigue. We aimed to characterize relationships between fatigue, other health status measures assessed with the Patient Reported Outcomes Measurement Information System (PROMIS) instruments, and accelerometer-based PA measurements in patients with SLE. The internal consistency of each PROMIS measure in our SLE sample was also evaluated. Methods This cross-sectional study analyzed 123 adults with SLE. The primary fatigue outcome was Fatigue Severity Scale (FSS) score. Secondary outcomes were Patient Reported Outcomes Measurement Information System (PROMIS) standardized T-scores in seven health status domains. Accelerometers were worn for seven days, and mean daily minutes of light, moderate/vigorous, and bouted (10 minutes) moderate/vigorous PA were estimated. Cronbach’s alpha was determined for each PROMIS measure to assess internal consistency. Relationships between FSS, PROMIS, and PA were summarized with Spearman partial correlation coefficients (r), adjusted for average daily accelerometer wear time. Results Mean FSS (4.3, SD 1.6) was consistent with clinically relevant levels of fatigue. Greater daily and bouted moderate/vigorous PA minutes correlated with lower FSS (r=−0.20, p=0.03 and r=−0.30, p=0.0007, respectively). For PROMIS, bouted moderate/vigorous PA minutes correlated with less fatigue (r=−0.20, p=0.03). PROMIS internal consistency was excellent, with Cronbach’s alpha >0.90 for each domain. Mean PROMIS T-scores for fatigue, pain interference, anxiety, sleep disturbance, sleep-related impairment, and physical function were worse than reported for the general U.S. population. More moderate/vigorous PA minutes were associated with less pain interference (r=−0.22, p=0.01). Both light PA and moderate/vigorous PA minutes correlated with better physical function (r=0.19, p=0.04 and r=0.25, p=0.006, respectively). Conclusion More time spent in moderate/vigorous PA was associated with less fatigue (FSS and PROMIS), less pain interference, and better physical function (PROMIS). PROMIS had excellent internal consistency in our SLE sample, and six of seven PROMIS measures indicated poorer average health status in SLE patients compared to the general U.S. population.

One challenge in caring for patients with systemic lupus erythematosus (SLE) is a paucity of approved therapeutics for treatment of the diverse disease manifestations. In the last 60 years, only one drug, belimumab, has been approved for SLE treatment. Critical evaluation of investigator initiated and pharma-sponsored randomized controlled trials (RCTs) highlights barriers to successful drug development in SLE, including disease heterogeneity, inadequate trial size or duration, insufficient dose finding before initiation of large trials, handling of background medications, and choice of primary endpoint. Herein we examine lessons learned from landmark SLE RCTs and subsequent advances in trial design, as well as discuss efforts to address limitations in current SLE outcome measures that will improve detection of true therapeutic responses in future RCTs.

Successful management of complex conditions such as systemic lupus erythematosus, SLE, and comorbid conditions benefit significantly from patient-reported outcomes (PRO) instruments that validly and precisely measure relevant aspects of health status (e.g., symptoms) and health related quality of life. Measuring health related quality of life and other aspects of health status (e.g., symptoms, functioning) with PROs provides SLE patients with an opportunity to participate in their treatment and to facilitate better communication with the multi-disciplinary team of health professionals involved in their care. Health outcomes research has produced a number of well-validated instruments that can be used across diseases whereas some have been specifically developed for SLE. The use of either a generic and SLE-specific PRO depends on the particular needs of a variety of clinical applications including population monitoring, treatment decision-making in clinical practice, clinical trials research, and for evaluating and comparing the effect of therapies across conditions, therapies, trials and patients in clinical research studies.

Physical activity ameliorates fatigue in systemic lupus erythematosus (SLE) patients by an unknown mechanism. Adipokines, which are influenced by adiposity and physical activity, may be associated with patient-reported fatigue. We describe cross-sectional associations between adipokines and fatigue, physical activity, and SLE disease activity. We measured adipokines, self-reported fatigue, and objective physical activity in 129 SLE patients. Fatigue was assessed with the Fatigue Severity Scale (FSS) and Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue score. Disease activity was measured with the Safety of Estrogens in Systemic Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI). Participants wore an accelerometer for 7 days to measure physical activity. Leptin, adiponectin, and resistin were measured in stored serum with a Luminex bead-based assay. Multivariable regression models assessed relationships between fatigue and adipokines, and Spearman correlation coefficients summarized associations between adipokines, physical activity, and SELENA-SLEDAI. Median adipokine levels were: leptin 30.5 ng/ml (Interquartile Range 14.0, 56.6), adiponectin 11.6 μg/ml (7.2, 16.8) and resistin 1.4 ng/ml (1.0, 2.2). Associations between adipokines and FSS or PROMIS fatigue were not significant. Body mass index (BMI) ≥ 30 kg/m was associated with FSS and PROMIS fatigue in regression analyses (p < 0.05). Weak correlations between leptin, adiponectin, leptin/adiponectin (L/A) ratio, and physical activity and between adiponectin and SELENA-SLEDAI score were not significant after adjusting for BMI. Adipokines were not associated with fatigue in SLE. Adipokines were correlated with physical activity (leptin, adiponectin, L/A ratio) and SLE disease activity (adiponectin), but most of these associations were explained by BMI.

Fatigue impacts 80-90% of patients with systemic lupus erythematosus (SLE), and an incomplete understanding of fatigue mechanisms limits effective treatment. Disease activity indices and laboratory markers inconsistently correlate with fatigue severity in SLE populations. Identification of fatigue biomarkers has important implications for understanding pathogenesis and defining novel therapeutic targets, but a paucity of evidence exists for fatigue biomarkers in SLE. The evidence for adipokines, reduced glutathione, iron deficiency, and vitamin D as potential biomarkers for SLE-related fatigue are reviewed. To address gaps in the SLE literature, the experience of each fatigue biomarker in other diseases is examined. Finally, biomarker associations with SLE pathogenesis and disease activity are discussed, as further rationale for investigation among SLE patients.