Fatigue may explain how disease activity erodes quality of life in rheumatic diseases

Fatigue appears to carry much of the burden that active rheumatic disease imposes on physical quality of life, according to a study of 807 patients with established rheumatic conditions published in the Journal of Behavioral Medicine.

Rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis substantially impair health-related quality of life, yet the pathways connecting laboratory and clinical measures of disease activity to how patients actually feel and function have remained incompletely mapped. The new analysis addressed this gap by quantifying how much of the statistical association between disease activity and physical quality-of-life scores runs through fatigue, a symptom patients frequently rank among their most disabling.

The cohort comprised 807 patients with established rheumatic disease.

In such models, mediation asks whether an exposure, here disease activity, influences an outcome, the physical HRQoL domain, partly through an intermediate variable, fatigue. Moderation asks whether a third variable, such as sex or treatment line, alters the strength of the association. Comorbidities were treated as covariates whose potential confounding influence could be adjusted for statistically.

The results showed that disease activity was significantly associated with all physical HRQoL dimensions, with p values below 0.001. Fatigue partially mediated these associations across all diseases and all HRQoL domains, with p values below 0.05. The proportion of the association attributable to fatigue varied considerably by domain. The highest percentage of explained variance appeared on the Role-Physical domain, ranging from 30.7 to 40.5 percent, followed by General Health at 26.1 to 28.0 percent, Physical Functioning at 14.0 to 23.5 percent, the Physical Component Score at 14.1 to 22.6 percent, and Bodily Pain at 13.3 to 21.9 percent.

These figures suggest that the imprint of active inflammation on a patient’s ability to sustain daily roles and on their perceived general health is transmitted to a substantial degree through the experience of fatigue. In practical terms, two patients with identical disease activity scores might report different physical quality of life depending on how fatigued they feel, and the study’s mediation estimates quantify how much of the overall association fatigue accounts for in each domain.

The moderation analyses yielded a largely null picture, with one exception. Rheumatological treatment moderated the association between DAPSA, the psoriatic arthritis activity index, and Bodily Pain, with first-line therapy showing a stronger positive association than second-line therapy. Sex was not a significant moderator of any of the tested pathways, and comorbidities, analyzed as covariates, were not significant moderators either. This indicates that the fatigue-mediated pathway operated similarly in men and women and was not fundamentally reshaped by the presence of additional health conditions.

The authors were explicit about the limits of interpretation. Because the study used a cross-sectional design, capturing patients at a single point in time, the proposed mediation approach may not be interpreted as a causal mechanism. A longitudinal design, they wrote, will be needed to conduct formal testing of the causal pathway. Cross-sectional mediation can demonstrate that the statistical pattern is consistent with a mediator, but it cannot establish that disease activity precedes fatigue or that fatigue precedes the decline in physical quality of life, since all variables were measured simultaneously.

Within those constraints, the findings carry a clear message for both researchers and clinicians. Fatigue could significantly account for the disease burden that patients with rheumatic diseases experience, the authors concluded, meaning that composite disease activity scores alone may understate the symptom load that actually drives physical quality of life. If future longitudinal studies confirm the mediated pathway, interventions targeting fatigue, whether through better control of inflammation, exercise, sleep management or psychological support, could become a more explicit focus of rheumatological care alongside traditional disease activity targets.

The study also demonstrates the value of condition-specific activity indices combined with a common quality-of-life instrument. By applying DAS28-CRP, DAPSA and ASDAS-CRP within the same analytic framework and scoring fatigue and physical HRQoL identically across diseases, the researchers could compare the mediated pathway across rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis rather than treating each condition in isolation. The consistency of partial mediation across all diseases and domains, despite the differing indices, strengthens the case that fatigue is a shared transducer of disease burden in inflammatory rheumatic conditions, one that formal longitudinal testing will now need to confirm.

Subject of Research: Cross-sectional mediation-moderation analysis of fatigue as a mediator between disease activity and physical health-related quality of life in rheumatic diseases

Article Title: Exploring fatigue as a factor linking disease activity to health-related quality of life in rheumatic diseases: a proposal of mediation-moderation analysis

Article References: Ristić, B., Bonetto, C., Fracassi, E., Maggioni, L., Cateni, V., Cristofalo, D., Gabrielli, B., Rossini, M., Carletto, A., & Tosato, S. (2026). Exploring fatigue as a factor linking disease activity to health-related quality of life in rheumatic diseases: a proposal of mediation-moderation analysis. Journal of Behavioral Medicine. https://doi.org/10.1007/s10865-026-00717-8

Image Credits: AI Generated

DOI: 10.1007/s10865-026-00717-8

Keywords: rheumatic diseases, fatigue, disease activity, health-related quality of life, rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, SF-36, mediation analysis, cross-sectional study, DAS28-CRP, comorbidities