NIHR Signal Existing drugs for rheumatoid arthritis may also improve associated fatigue

Published on 23 August 2016

Biological treatments for moderate to severe rheumatoid arthritis appear to reduce fatigue as well as other symptoms. Although existing studies looking at effectiveness have focused on symptoms such as pain, their combined results suggest this additional benefit.

Biological treatments work by reducing the joint inflammation and destruction associated with the condition, but to date it has been uncertain if this could affect fatigue.

Fatigue was not a main outcome in any of the included studies in this Cochrane review. The way it was measured and reported varied between studies, making it harder to compare findings.

Overall, these drugs seem to give a small to moderate reduction in fatigue, which may be an important consideration for patients and prescribers.

Existing drugs for rheumatoid arthritis may also improve associated fatigue

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Why was this study needed?

Rheumatoid arthritis affects around 400,000 people in the UK.  It is an autoimmune disease in which the person’s own immune system attacks their body, in this case mainly the joints, causing inflammation, swelling, stiffness, pain and irreversible joint damage.

There is no cure for rheumatoid arthritis. Treatments such as anti-inflammatory painkillers aim to relieve symptoms while drugs such as methotrexate and biologicals aim to slow down the disease process and prevent joint damage. Biological treatments only became available recently. They are more expensive and usually only used when traditional treatments such as methotrexate have not been effective.

Fatigue is often reported by patients as a symptom that has a significant impact upon their quality of life. However, it has not been a main outcome in studies that look at how well rheumatoid arthritis treatments work. This review aimed to address this issue by focusing on whether patients’ fatigue was affected by the use of biological treatments.

What did this study do?

This systematic review included 32 studies, 30 of which were double-blind randomised placebo-controlled trials that looked at whether biologic treatment for rheumatoid arthritis in adults has an effect on fatigue. The results of these trials were pooled in a meta-analysis.In total 9,946 participants received biological treatmentsand 4,682 participants received either placebo, usual care or another treatment.The follow-up for most studies was 24 weeks or less.

Biological agents included; infliximab, etanercept, adalimumab, certolizumabpegol, golimumab, rituximab, abatacept, tocilizumab, canakinumab and anti-interferon-gamma monoclonal antibodies.

Fatigue was a secondary outcome in the included studies, which means that it was not the main interest for the underlying studies and the results are selective and less reliable. In addition, despite being of gold standard study design, the studies were collectively downgraded from high to medium quality because of selective reporting bias.

What did it find?

  • Biological treatments moderately reduced fatigue (standardised mean difference -0.43, 95% confidence interval [CI] -0.38 to -0.49).
  • The size of this effect is clinically useful. Five people would need to be treated with biologics for one person to see a small to moderate reduction in fatigue (number needed to treat 5 [95% CI 5 to 6]).
  • These pooled results need to be treated with some caution as there was statistical variability between studies. This means that the trials may have differed on things like drug dosage, proportion with early disease or comorbidities like depression.
  • Adverse effects of biological agents were going to be an outcome measure in this study but have subsequently been included in a separate Cochrane review.

What does current guidance say on this issue?

There is no current guidance that specifically looks at fatigue in rheumatoid arthritis. The National Institute for Health and Care Excellence (NICE) is currently updating the guideline on the management of rheumatoid arthritis in adults. The 2012 guideline refers readers to four NICE technology appraisals for more detailed guidance on the use of biological treatments. Overall these recommend the use of biological treatments for severe cases of rheumatoid arthritis and when other front line treatments have failed. This is largely because biological treatments are more expensive than older drugs.

What are the implications?

Biological agents do seem to reduce fatigue in patients with high levels of disease symptoms. Exactly how this occurs is still uncertain. As fatigue was only a secondary outcome in the included studies and the populations studied differed, it is difficult to know whether changes in fatigue are directly due to the intervention or perhaps could have occurred due to different doses of drugs, or stages of disease for example.

This is an area that people with rheumatoid arthritis feel has a significant impact upon their quality of life. Although the exact size of an effect might be small to moderate it seems that for people considering taking these drugs, the knowledge that fatigue might be helped could be useful.

Citation and Funding

Almeida C, Choy EH, Hewlett S, et al. Biologic interventions for fatigue in rheumatoid arthritis. Cochrane Database Syst Rev. 2016;6:CD008334.

Cochrane UK and the Musculoskeletal Cochrane Review Group are supported by NIHR infrastructure funding.

Bibliography

NHS Choices. Rheumatoid arthritis. London: Department of Health; updated 2014.

NICE. Rheumatoid arthritis in adults: management.CG79. London: National Institute for Health and Care Excellence; 2012.

NICE. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. TA195. London: National Institute for Health and Care Excellence; 2010.

NICE. Adalimumab, etanercept, infliximab, certolizumabpegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed.TA375. London: National Institute for Health and Care Excellence; 2016.

NICE. Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs. TA225. London: National Institute for Health and Care Excellence; 2011.

NICE. Tocilizumab for the treatment of rheumatoid arthritis. TA247. London: National Institute for Health and Care Excellence; 2012.

Why was this study needed?

Rheumatoid arthritis affects around 400,000 people in the UK.  It is an autoimmune disease in which the person’s own immune system attacks their body, in this case mainly the joints, causing inflammation, swelling, stiffness, pain and irreversible joint damage.

There is no cure for rheumatoid arthritis. Treatments such as anti-inflammatory painkillers aim to relieve symptoms while drugs such as methotrexate and biologicals aim to slow down the disease process and prevent joint damage. Biological treatments only became available recently. They are more expensive and usually only used when traditional treatments such as methotrexate have not been effective.

Fatigue is often reported by patients as a symptom that has a significant impact upon their quality of life. However, it has not been a main outcome in studies that look at how well rheumatoid arthritis treatments work. This review aimed to address this issue by focusing on whether patients’ fatigue was affected by the use of biological treatments.

What did this study do?

This systematic review included 32 studies, 30 of which were double-blind randomised placebo-controlled trials that looked at whether biologic treatment for rheumatoid arthritis in adults has an effect on fatigue. The results of these trials were pooled in a meta-analysis.In total 9,946 participants received biological treatmentsand 4,682 participants received either placebo, usual care or another treatment.The follow-up for most studies was 24 weeks or less.

Biological agents included; infliximab, etanercept, adalimumab, certolizumabpegol, golimumab, rituximab, abatacept, tocilizumab, canakinumab and anti-interferon-gamma monoclonal antibodies.

Fatigue was a secondary outcome in the included studies, which means that it was not the main interest for the underlying studies and the results are selective and less reliable. In addition, despite being of gold standard study design, the studies were collectively downgraded from high to medium quality because of selective reporting bias.

What did it find?

  • Biological treatments moderately reduced fatigue (standardised mean difference -0.43, 95% confidence interval [CI] -0.38 to -0.49).
  • The size of this effect is clinically useful. Five people would need to be treated with biologics for one person to see a small to moderate reduction in fatigue (number needed to treat 5 [95% CI 5 to 6]).
  • These pooled results need to be treated with some caution as there was statistical variability between studies. This means that the trials may have differed on things like drug dosage, proportion with early disease or comorbidities like depression.
  • Adverse effects of biological agents were going to be an outcome measure in this study but have subsequently been included in a separate Cochrane review.

What does current guidance say on this issue?

There is no current guidance that specifically looks at fatigue in rheumatoid arthritis. The National Institute for Health and Care Excellence (NICE) is currently updating the guideline on the management of rheumatoid arthritis in adults. The 2012 guideline refers readers to four NICE technology appraisals for more detailed guidance on the use of biological treatments. Overall these recommend the use of biological treatments for severe cases of rheumatoid arthritis and when other front line treatments have failed. This is largely because biological treatments are more expensive than older drugs.

What are the implications?

Biological agents do seem to reduce fatigue in patients with high levels of disease symptoms. Exactly how this occurs is still uncertain. As fatigue was only a secondary outcome in the included studies and the populations studied differed, it is difficult to know whether changes in fatigue are directly due to the intervention or perhaps could have occurred due to different doses of drugs, or stages of disease for example.

This is an area that people with rheumatoid arthritis feel has a significant impact upon their quality of life. Although the exact size of an effect might be small to moderate it seems that for people considering taking these drugs, the knowledge that fatigue might be helped could be useful.

Citation and Funding

Almeida C, Choy EH, Hewlett S, et al. Biologic interventions for fatigue in rheumatoid arthritis. Cochrane Database Syst Rev. 2016;6:CD008334.

Cochrane UK and the Musculoskeletal Cochrane Review Group are supported by NIHR infrastructure funding.

Bibliography

NHS Choices. Rheumatoid arthritis. London: Department of Health; updated 2014.

NICE. Rheumatoid arthritis in adults: management.CG79. London: National Institute for Health and Care Excellence; 2012.

NICE. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. TA195. London: National Institute for Health and Care Excellence; 2010.

NICE. Adalimumab, etanercept, infliximab, certolizumabpegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed.TA375. London: National Institute for Health and Care Excellence; 2016.

NICE. Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs. TA225. London: National Institute for Health and Care Excellence; 2011.

NICE. Tocilizumab for the treatment of rheumatoid arthritis. TA247. London: National Institute for Health and Care Excellence; 2012.

Biologic interventions for fatigue in rheumatoid arthritis

Published on 9 June 2016

Almeida, C.,Choy, E. H.,Hewlett, S.,Kirwan, J. R.,Cramp, F.,Chalder, T.,Pollock, J.,Christensen, R.

Cochrane Database Syst Rev Volume 6 , 2016

BACKGROUND: Fatigue is a common and potentially distressing symptom for patients with rheumatoid arthritis (RA), with no accepted evidence-based management guidelines. Evidence suggests that biologic interventions improve symptoms and signs in RA as well as reducing joint damage. OBJECTIVES: To evaluate the effect of biologic interventions on fatigue in rheumatoid arthritis. SEARCH METHODS: We searched the following electronic databases up to 1 April 2014: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Current Controlled Trials Register, the National Research Register Archive, The UKCRN Portfolio Database, AMED, CINAHL, PsycINFO, Social Science Citation Index, Web of Science, and Dissertation Abstracts International. In addition, we checked the reference lists of articles identified for inclusion for additional studies and contacted key authors. SELECTION CRITERIA: We included randomised controlled trials if they evaluated a biologic intervention in people with rheumatoid arthritis and had self reported fatigue as an outcome measure. DATA COLLECTION AND ANALYSIS: Two reviewers selected relevant trials, assessed methodological quality and extracted data. Where appropriate, we pooled data in meta-analyses using a random-effects model. MAIN RESULTS: We identified 32 studies for inclusion in this current review. Twenty studies evaluated five anti-tumour necrosis factor (anti-TNF) biologic agents (adalimumab, certolizumab, etanercept, golimumab and infliximab), and 12 studies focused on five non-anti-TNF biologic agents (abatacept, canakinumab, rituximab, tocilizumab and an anti-interferon gamma monoclonal antibody). All but two of the studies were double-blind randomised placebo-controlled trials. In some trials, patients could receive concomitant disease-modifying anti-rheumatic drugs (DMARDs). These studies added either biologics or placebo to DMARDs. Investigators did not change the dose of the latter from baseline. In total, these studies included 9946 participants in the intervention groups and 4682 participants in the control groups. Overall, quality of randomised controlled trials was moderate with a low to unclear risk of bias in the reporting of the outcome of fatigue. We downgraded the quality of the studies from high to moderate because of potential reporting bias (studies included post hoc analyses favouring reporting of positive result and did not always include all randomised individuals). Some studies recruited only participants with early disease. The studies used five different instruments to assess fatigue in these studies: the Functional Assessment of Chronic Illness Therapy Fatigue Domain (FACIT-F), Short Form-36 Vitality Domain (SF-36 VT), Visual Analogue Scale (VAS) (0 to 100 or 0 to 10) and the Numerical Rating Scale (NRS). We calculated standard mean differences for pooled data in meta-analyses. Overall treatment by biologic agents led to statistically significant reduction in fatigue with a standardised mean difference of -0.43 (95% confidence interval (CI) -0.38 to -0.49). This equates to a difference of 6.45 units (95% CI 5.7 to 7.35) of FACIT-F score (range 0 to 52). Both types of biologic agents achieved a similar level of improvement: for anti-TNF agents, this stood at -0.42 (95% CI -0.35 to -0.49), equivalent to 6.3 units (95% CI 5.3 to 7.4) on the FACIT-F score; and for non-anti-TNF agents, it was -0.46 (95% CI -0.39 to -0.53), equivalent to 6.9 units (95% CI 5.85 to 7.95) on the FACIT-F score. In most studies, the double-blind period was 24 weeks or less. No study assessed long-term changes in fatigue. AUTHORS' CONCLUSIONS: Treatment with biologic interventions in patients with active RA can lead to a small to moderate improvement in fatigue. The magnitude of improvement is similar for anti-TNF and non-anti-TNF biologics. However, it is unclear whether the improvement results from a direct action of the biologics on fatigue or indirectly through reduction in inflammation, disease activity or some other mechanism.

Expert commentary

When most people think about arthritis, they think about pain. But rheumatoid arthritis can also cause severe exhaustion, compared by some with the condition to having bad flu, every single day. The impact of fatigue on wellbeing, ability to participate in everyday life or go to work is huge and people with arthritis consider it as important a symptom as pain. We don’t routinely measure fatigue in clinical practice, though, or allow it to inform clinical decisions. If biologic drugs can have such an impact, maybe it’s time we did?

Dr Benjamin Ellis, Consultant Rheumatologist, Charing Cross Hospital; Senior Clinical Policy Advisor, Arthritis Research UK