LIVERPOOL, ENGLAND – Anti–tumor necrosis factor treatment significantly decreased fatigue in patients with rheumatoid arthritis in an analysis of data from the British Society for Rheumatology Biologics Registers Rheumatoid Arthritis Register.
Of 6,835 patients included in the analysis, 38.8% reported high levels of fatigue at baseline, which was defined as a score of 12.5 or less on the vitality domain of the Short Form (SF)-36. Of these, 66% reported clinically relevant improvements of 10 U or more on the SF-36 vitality domain 6 months after starting anti–tumor necrosis factor (TNF) treatment.
"Randomized controlled trials have shown modest improvements in fatigue with anti-TNF therapy, but fatigue has not been the primary research question in these trials, and so that led us to ask what the effect would be in patients who had clinically relevant symptoms," said Katie Druce, who performed the research as part of her postgraduate studies at the University of Aberdeen (Scotland).
Data on 13,122 patients with RA who started treatment with etanercept, adalimumab, or infliximab between 2000 and 2008 were initially considered, but only those who had data on fatigue available at baseline and at 6-month assessments were included in the analysis.
At baseline, the mean age of participants was 57 years, and most (77%) were female and white (97%). A total of 31% were not working because of illness. The patients had mean scores of 6.57 on the 28-joint Disease Activity Score, 21.1 on the bodily pain and 24.8 on the vitality domains of the SF-36, and 2.03 on the mean Health Assessment Questionnaire Disability Index.
Fatigue improved at 6 months
Ms. Druce reported at the British Society for Rheumatology (BSR) annual conference that there was an absolute improvement in fatigue at 6 months of 22.5 U in the 2,652 patients who had reported a high level of fatigue at baseline. This exceeded the value of 10 U or more that was conservatively set as the minimum clinically important difference (MCID). Furthermore, in the patients who improved – that is going from a high level to a low level of fatigue – the difference was even greater, with improvement three times the MCID, at about 32 U.
Baseline predictors of improvement included being in good mental health, no history of hypertension or depression, and not being unemployed because of ill health. Other predictors included being female, rheumatoid factor positive, having a low level of disability, and not using steroids. Patients with multiple baseline predictors of improvement appeared to have the largest absolute improvement in fatigue at 6 months.
"Importantly, we saw no association with disease activity or measures of inflammation," Ms. Druce said, and the specific anti-TNF drug used was also not influential on the findings. She noted that baseline predictors of fatigue might be able to help stratify patients who need specific fatigue management.
Pain drives fatigue in RA
The improvements in RA-related fatigue seen with biologic therapy were driven by decreases in pain and not disease activity, Ms. Druce said, reporting the finding of a separate analysis elsewhere at the conference.
"Anecdotally, from both clinicians and patients, we know that they consider fatigue to be caused by disease activity, but when we look at the evidence from the literature, we see that there is an inconsistent link between fatigue and disease activity," she said. "Yet we know that fatigue improves after anti-TNF therapy commences. So this led us to look at which variables are driving change in fatigue that we see after anti-TNF therapies are commenced," she said.
Ms. Druce and her colleagues used structural equation modeling, which evaluates the effect of one variable on an outcome and the pathway by which it has that effect, to find that for every 1–standard deviation increase in change in disease activity, there was a 0.05 increase in change in fatigue. Although this does indicate some improvement, change in pain had a greater effect, with every 1–standard deviation increase in change in pain linked to a 0.31 increase in change in fatigue.
"What we found was that 82% of the effect of change in disease activity is mediated through other variables in [our] model," Ms. Druce explained. Indeed, it was found that almost two-thirds of the change in fatigue was mediated by pain (or pain and mental health), 27% through disability (or disability and mental health), and 9% directly through mental health.
"This led us to conclude that improvements in fatigue after commencing anti-TNF therapies are driven by improvements in pain rather than directly from disease activity, but that mental health and disability are also important, and, along with pain, represent potentially modifiable factors for us to target in routine treatment," Ms. Druce said.