Fatigue in rheumatoid arthritis reflects pain,

not disease activity

04/07/06: LC Pollard, EH Choy, J Gonzalez, B Khoshaba, DL Scott. Department of Rheumatology King’s College London School of Medicine at King’s College Hospital

Introduction

Fatigue is a common symptom in rheumatoid arthritis (RA), and interviews with RA patients have highlighted its importance [1,2]. Between 40-80% of RA patients who attend hospital outpatients have significant levels of fatigue [3-6]. Despite this, there has been little research into what causes fatigue in RA.

However, a study using an anti-Tumour Necrosis Factor (TNF) drug showed that following treatment, there was a significant reduction in fatigue [7]. There is a small amount of data to suggest that conventional disease modifying drugs (DMARDs) like methotrexate improve fatigue.

Previous studies have shown that several factors may influence fatigue including pain and depression [3,4,6,8-17] how people perceive their illness and their general health beliefs, as well as poor social support [8,9].

Our aim in this study was to look at how much active disease (inflammation) in RA contributes to fatigue compared to other factors such as pain and depression. We also looked at the effect of anti-TNF treatment and DMARDs on fatigue in RA.

Methods

We looked at two groups (238 patients in first group, 274 patients in second group) of patients to identify the contributors to fatigue in RA and also studied fatigue in patients following six months of treatment with DMARDs (54 patients) and after 3 months of treatment with anti-TNF therapy (30 patients).

Fatigue was measured using a visual analogue scale (VAS) – a line which measures 100mm, patients are asked to mark on the line how much fatigue they have been experiencing in the last seven days:

0  - 100  0= No fatigue at all  -  100 =Extremely Fatigued

In the second group of patients we also used a second measure of fatigue by asking 4 questions about their energy levels over the previous 4 weeks (SF-36 vitality subscale) [18]:

• Did you feel full of pep?
• Did you feel worn out?
• Did you have a lot of energy?
• Did you feel tired?

The responses ranged from 1 (all of the time) to 5 (none of the time). These answers are then transformed to give a score from 0-100, with lower scores indicating more fatigue.

We also assessed disease activity, including numbers of tender and swollen joints, duration of morning stiffness, erythrocyte sedimentation rate (ESR), patient assessment of disease activity, pain, health assessment questionnaire (HAQ) – which measures disability [19], presence of other illnesses and all other medications being taken.

Results

• 80% of patients had clinically relevant levels of fatigue (score of 20mm or more on VAS) and over 50% had high fatigue levels (score of 50mm or more on VAS)
• The average fatigue score using the SF-36 vitality subscale was 51 (normal population scores range from 61-65) indicating higher fatigue than the general population.
• Fatigue correlated with a number of variables individually (pain, disease activity, depression, fibromyalgia, methotrexate, paracetamol and tramadol). These relationships were similar for the VAS scores and the SF-36 vitality scores.
• Using multiple regression analysis (we included all variables in the analysis to determine which of the variables had the most effect on fatigue) we found that pain, HAQ (health assessment questionnaire, a measure of disability) and depression had the dominant effect. Patients receiving methotrexate had less fatigue.
• The second group of patients showed similar results, with pain, HAQ, depression and the patients’ assessment of disease predicting fatigue.
• Following 6 months of treatment with DMARDs fatigue levels fell but this was not statistically significant. (56mm on VAS to 49mm)
• Fatigue levels in patients prior to receiving anti-TNF therapy were significantly higher than those levels seen in patients prior to DMARD therapy.
• Following 3 months of treatment with anti-TNF therapy there were greater reductions in fatigue levels and these reached statistical significance. (67 mm on VAS to 50mm)
• The reduction in fatigue levels in both treatment groups mirrored reductions in pain and disease activity

Conclusions

Fatigue is a common, debilitating symptom in many patients with RA. We have shown that it is strongly associated with pain. Patients with active RA have high levels of fatigue also but when all the variables are analysed together in a multiple regression analysis, this relationship was less important than the association with pain. Patients diagnosed with depression also had higher levels of fatigue but no other illnesses had a direct relationship. HAQ also correlated with fatigue suggesting that patients with high fatigue levels are markedly disabled. Methotrexate use was associated with less fatigue suggesting that patients who received methotrexate had a better outcome or that those patients not treated with methotrexate represent a specific group of RA patients who have higher fatigue levels.

Interestingly we found no association between fatigue and age or disease duration, suggesting that peripheral features such as muscle mass which decreases with age are unimportant in the development of fatigue. This would therefore suggest that fatigue originates centrally in the central nervous system.

Our studies showed that in routine clinical practice, fatigue levels fall when active RA is treated with anti-TNF therapy and to a lesser extent with DMARDs. These falls mirror reductions in disease activity and pain. TNF has been implicated in pain pathways in the central nervous system [20] and thus the improvement in pain and fatigue seen with anti-TNF therapy may be due to a direct effect centrally via sensory neurons.

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