Determining Pathways to Improvements in Fatigue in Rheumatoid Arthritis: Results From the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

Abstract

Objective There is debate as to the role of inflammatory disease activity in the etiology of rheumatoid arthritis (RA)–related fatigue. We undertook this study to determine the relationship of fatigue to disease activity by examining pathways associated with change in fatigue in subjects starting anti–tumor necrosis factor (anti‐TNF) therapy for the first time. Methods Participants who had been recruited to the British Society for Rheumatology Biologics Register for RA provided information on fatigue (Short Form 36 [SF‐36] vitality scale) and other health status variables at the start of anti‐TNF therapy and 6 months later. The Disease Activity Score in 28 joints (DAS28) and inflammation (erythrocyte sedimentation rate [ESR]/C‐reactive protein [CRP] level) were also reported. A path analysis model comprising changes in fatigue, pain, disease activity, disability, and mental health, along with effects of sex and a history of depression, was used to examine those with high levels of fatigue at baseline (score of ≤12.5 units on the SF‐36 vitality scale). The DAS28 was substituted for ESR/CRP to delineate the specific role of inflammation. Results With a total of 2,652 participants, we identified a well‐fitting model (χ2 = 0.18, P = 0.98) accounting for 40% of the variance in fatigue change. There was no direct pathway from change in inflammation to change in fatigue; instead, significant pathways to change in fatigue were observed from changes in disease activity, pain, mental health, and disability, along with effects of sex and a history of depression. A total of 82% of the effect of change in disease activity was indirect, of which ∼50% was mediated through a change in pain. Conclusion Improvements in fatigue do not appear to be driven by inflammatory disease activity; instead, they appear to result indirectly from improvements in pain. Additional significant pathways through disability and mental health suggest potentially modifiable factors that could be targeted to improve clinically important levels of fatigue.

Interpretation of DAS28 and its components in the assessment of inflammatory and non-inflammatory aspects of rheumatoid arthritis

“…Self-reported fatigue and poor mental health scores are associated with worse pain and greater central sensitisation in people with RA [38,39]. DAS28-ESR was significantly associated with fatigue and mental health in each study group.…”

Examining Changes in Central and Peripheral Pain as Mediates of Fatigue Improvement: Results From the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

“…Although there is evidence that fatigue responds in the short term to interventions that target inflammatory mediators of disease (4,5), there is a paucity of evidence supporting such associations in the long term (1,6).…”

“…To more specifically investigate the possible mechanisms of fatigue change, path analysis was undertaken and showed that improvements in fatigue are mediated by reductions in pain, rather than caused directly by changes in inflammatory disease activity (6). This result implies a need to target pain more specifically to improve fatigue management in the future, but pain has a complicated etiology (7), and while anti-TNF therapies are known to reduce pain caused by peripheral inflammation, evidence increasingly shows that they may modify central pain mechanisms in the central nervous system (8,9).…”

Fatigue in early, intensively treated and tight-controlled rheumatoid arthritis patients is frequent and persistent: a prospective study

“…The direction of the association, thus is depression induced by fatigue or fatigue induced by depression, is under debate. According to Druce et al, both directions are possible [39]. A dynamic conceptual model of RA fatigue showed the bi-directional relation for depression and fatigue [40].…”