Background/Purpose: Rheumatoid Arthritis (RA) patients commonly report reductions in fatigue after commencing Anti-TNF therapy. The mechanisms behind such reductions have not been determined, although it is assumed that changes in disease activity drive improvements. Nevertheless, to promote improvement in this patient priority, the true pathways to change in fatigue must be elucidated. Using Structural Equation Modelling (SEM), this study aimed to be the first to determine the pathways to improvement in fatigue among RA patients commencing Anti-TNF therapy.

Methods: Participants recruited to a long-term cohort study (the British Society for Rheumatology Biologics Register for RA) provided information on fatigue (SF 36 Vitality), disease activity (DAS 28) and other putative mediators of fatigue change (including disability, pain and mental health) at Anti-TNF therapy commencement and 6 month follow-up. A SEM path model, using the data of 2652 participants with high baseline fatigue (SF 36 Vitality ≤12.5,), was constructed employing a model generation approach. The total, direct and indirect effects of each putative mediator on improvement in fatigue were quantified using path co-efficients. Where indirect effects accounted for more than 50% of total effect, the variable was considered to be mediated by other variables in the model.

Results: Significant pathways to improvement in fatigue (Figure 1) were shown to originate from changes in disease activity, pain, mental health, and disability, as well as a history of depression and participant sex. The model accounted for 40% of the variance in change in fatigue and demonstrated a good model fit (χ²=0.18, df=3,p=0.98). The largest absolute improvements in fatigue were associated with a one standard deviation improvement in pain and mental health (0.31 and 0.28 unit improvement in fatigue, respectively). As 82% of the total effect of change in disease activity was indirect, the variable was mediated by other variables in the model. Specifically, 50% of the indirect effect was mediated through a change in pain and an additional 14% through pain and mental health improvement. 

Conclusion: Improvement in RA related fatigue after commencing Anti-TNF therapy is driven by reductions in pain, rather than directly from disease activity. In addition, mental health and disability are important mediators in the pathway to fatigue improvement and should be targeted, in an attempt to further improve this patient priority.