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Non-pharmacological interventions for fatigue in rheumatoid arthritis

  1. Fiona Cramp1,*,
  2. Sarah Hewlett1,
  3. Celia Almeida1,
  4. John R Kirwan2,
  5. Ernest HS Choy3,
  6. Trudie Chalder4,
  7. Jon Pollock1,
  8. Robin Christensen5

Editorial Group: Cochrane Musculoskeletal Group

Published Online: 23 AUG 2013

Assessed as up-to-date: 1 OCT 2012

DOI: 10.1002/14651858.CD008322.pub2


How to Cite

Cramp F, Hewlett S, Almeida C, Kirwan JR, Choy EHS, Chalder T, Pollock J, Christensen R. Non-pharmacological interventions for fatigue in rheumatoid arthritis. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD008322. DOI: 10.1002/14651858.CD008322.pub2.

Author Information

  1. 1

    University of the West of England, Faculty of Health & Life Sciences, Bristol, UK

  2. 2

    University of Bristol, Bristol Royal Infirmary, Rheumatology Unit, Bristol, UK

  3. 3

    Cardiff University School of Medicine, Section of Rheumatology, Department of Medicine, Cardiff, UK

  4. 4

    Institute of Psychiatry, King's College London, Department of Psychological Medicine, London, UK

  5. 5

    Copenhagen University Hospital, Frederiksberg, Copenhagen, Denmark, Musculoskeletal Statistics Unit (MSU), The Parker Institute, Dept Rheumatology, Copenhagen, Denmark

*Fiona Cramp, Faculty of Health & Life Sciences, University of the West of England, Glenside campus, Blackberry Hill, Bristol, BS16 1DD, UK. fiona.cramp@uwe.ac.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 23 AUG 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

 
Summary of findings for the main comparison. Non-pharmacological interventions for rheumatoid arthritis

Non-pharmacological interventions for rheumatoid arthritis

Patient or population: patients with rheumatoid arthritis
Settings: All
Intervention: non-pharmacological interventions

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

(95% CI)

Assumed riskCorresponding risk

ControlNon-Pharmacological Interventions

fatigue (physical activity interventions)
Various fatigue scales
The mean fatigue in the control groups was
6.3 VAS (score: 0-10)
The mean fatigue (physical activity interventions) in the intervention groups was
9% lower
(2% to 15% lower)1
371
(6 studies)
⊕⊕⊕⊝
moderate3
SMD -0.36 (-0.62 to -0.10)

Relative percent change -13.7% (-23.6 to -3.8)

NNTB 7 (4 to 26)

fatigue (psychosocial interventions)
Various fatigue scales
The mean fatigue in the control groups was
6.3 VAS (score: 0-10)
The mean fatigue (psychosocial interventions) in the intervention groups was
6% lower
(2% to 10% lower)1,2
1,556
(13 studies)
⊕⊕⊝⊝
low3,4
SMD -0.24 (-0.40 to -0.07)

Relative percent change -9.1% (-15.2 to -2.7)

NNTB 10 (6 to 33)

fatigue (Andrographis paniculata)The mean fatigue in the control groups was
6.3 VAS (score: 0-10)
The mean fatigue (Andrographis Paniculata) in the intervention groups was
6% lower
(18% lower to 6% higher)1,2
58
(1 study)
⊕⊕⊝⊝
low5
SMD -0.25 (-0.77 to 0.27)

Relative percent change -9.5% (-29.3 to 10.3)

NNTB not applicable

fatigue (data tracker)The mean fatigue in the control groups was
6.3 VAS (score: 0-10)
The mean fatigue (data tracker) in the intervention groups was
1% higher
(2% lower to 5% higher)1,2
714
(1 study)
⊕⊕⊝⊝
low5
SMD 0.06 (-0.10 to 0.21)

Relative percent change 2.3% (-3.8 to 8.0)

NNTB not applicable

fatigue (Omega-3 Fatty acids)The mean fatigue in the control groups was
6.3 VAS (score: 0-10)
The mean fatigue (Omega-3 Fatty acids) in the intervention groups was
22% higher
(11% to 33% higher)1,2
81
(1 study)
⊕⊕⊝⊝
low6
SMD 0.93 (0.47 to 1.39)

Relative percent change 35.4% (17.9 to 53.0)

NNTB not applicable

fatigue (Mediterranean diet)The mean fatigue in the control groups was
6.3 VAS (score: 0-10)
The mean fatigue (Mediterranean diet) in the intervention groups was
9% higher
(4% lower to 22% higher)1,2
51
(1 study)
⊕⊕⊕⊝
moderate5
SMD 0.37 (-0.18 to 0.93)

Relative percent change 14.1% (-6.9 to 35.4)

NNTB not applicable

fatigue (reflexology)The mean fatigue in the control group was

6.3 VAS (score: 0-10)
The mean fatigue (Reflexolgy) in the intervention groups was
30% lower
(62% lower to 3% higher)1,2
11

(1 study)
⊕⊕⊝⊝
low4
SMD -1.24 (-2.59 to 0.11)

Relative percent change -47.2% (-98.7 to 4.2)

NNTB not applicable

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; SMD: standardised mean difference; NNTB: number needed to treat for an additional beneficial outcome

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 A lower score means less fatigue
2 Based on a conversion from Hewlett S et al (Mean: 6.3, SD: 2.4).
3 Limitations in the design as appropriate masking was not possible
4 Unexplained heterogeneity present between studies, represented by I2 of 55%
5 High probability of publication bias; only 1 study available; did not support a difference between groups
6 High probability of publication bias; only 1 study, differences between groups not assessed

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Description of the condition

Rheumatoid arthritis (RA) is an auto-immune, systemic, inflammatory condition causing pain and synovitis primarily in the joints of the hands and feet, but often involving additional joints (Conaghan 1999). Repeated flares of such disease activity cause symptoms of pain, fatigue, stiffness and long-term loss of function. People with a range of long-term conditions report clinically significant fatigue (for example multiple sclerosis, diabetes, stroke) and it has been identified by RA patients as a key problem, which they consider harder to manage than pain (Hewlett 2005). Quantitative studies consistently show that fatigue occurs in up to 70% of RA patients in the UK (almost 0.4 million people), and is as common and severe as pain (Department of Health 2006; Wolfe 1996). Fatigue has been identified by people with RA as a major concern (Hewlett 2005) and international consensus has been reached that it should be measured in all clinical trials (Kirwan 2007). Specifically, in 2008, participants including patients at OMERACT (Outcome Measures in Rheumatology) endorsed fatigue as an addition to the 'core set' of outcome measures for all future studies, highlighting the importance of this symptom (Kirwan 2007).

RA fatigue is likely to be explained by multiple and complex pathways that vary between and within patients over time (Hewlett 2011a). There is currently mixed evidence for the explanatory role of inflammatory activity and it is likely that additional causal pathways include behavioural activities (for example boom and bust behaviours where the individual does too much when they have some energy, resulting in feeling more fatigued, and then has to rest for longer), deconditioning from disability, mood (for example anxiety, depression, helplessness), illness beliefs (for example unrealistic outlook), stress and pain (Hewlett 2008; Pollard 2006; Treharne 2009). It is possible that the mixed evidence also arises from the lack of RA-specific fatigue measures and is associated with the lack of an agreed fatigue definition at the time these studies were conducted (Hewlett 2011b).

 

Description of the intervention

Many non-pharmacological approaches to the management of RA fatigue are used. These centre largely around, but are not restricted to, self-management techniques based upon physical activity and psychosocial interventions. Non-pharmacological interventions may be initiated or supported by education programmes by the multi-disciplinary team using processes such as group education (Hewlett 2008). In terms of physical activity, interventions may include strategies to increase a person's overall daily activity level or the implementation of a specific exercise regime such as walking or cycling for a specific duration at a target intensity. Psychosocial interventions may include a range of talking therapies that are based upon a specific behaviour change theory. Previous Cochrane reviews have been carried out to investigate the effects of non-pharmacological interventions in RA (Brosseau 2005; Cameron 2011; Casimiro 2002; Casimiro 2005; Egan 2001; Hagen 2009; Han 2004; Hurkmans 2009; Pelland 2002; Silva 2010; Tuntland 2009; Verhagen 2004; Welch 2002) but none have specifically investigated the effects of these interventions on fatigue.

 

How the intervention might work

Non-pharmacological interventions may address several causal pathways at the same time. For example, education programmes may work by not only helping people to change behaviours that perpetuate RA fatigue or inhibit its self-management, through pacing and lifestyle management, but also by addressing mood and coping strategies. Exercise interventions may address physiological deconditioning (either muscular or respiratory) that are associated with disability or inactivity in RA. Interventions that address thoughts and feelings around fatigue may encourage helpful coping strategies, such as emotional expression, reprioritisation and work and life balance, and help patients reduce perceived stress and helplessness. In addition, the mode of delivery of such interventions that is effective in bringing about behaviour change needs to be identified. For example, it has been shown in other Cochrane reviews of group education in musculoskeletal disease that a cognitive-behavioural therapy approach is more likely to prompt the adoption of new behaviours than simple information giving (Riemsma 2003).

 

Why it is important to do this review

No systematic review of non-pharmacological interventions to help people manage their RA fatigue has been conducted, therefore the question of whether or not they work has not been answered. Interventions such as group education as reported in the literature are time-consuming and costly for patients and professionals, and need to be delivered in a way that results in behaviour change, therefore the evidence needs evaluating to enhance practice.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

To evaluate the benefit and harm of non-pharmacological interventions for the management of fatigue in people with rheumatoid arthritis. This included any intervention that was not classified as pharmacological in accordance with European Union (EU) Directive 2001/83/EEC.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled trials

 

Types of participants

Adults (usually over 18 years of age) with a diagnosis of RA either confirmed by a rheumatologist or using American College of Rheumatology (ACR) criteria (Arnett 1988).

 

Types of interventions

All non-pharmacological interventions, which encompassed all interventions other than those that were classified as pharmacological. Pharmacological interventions were classified as medicinal products in accordance with the EU Directive 2001/83/EEC (EU 2001) which states: "any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis".

Because of the large number of possible non-pharmacological interventions, each of which may have many synonyms, there was a risk of missing some interventions if only specific search terms were used. We therefore initially searched for any randomised controlled trial reporting RA fatigue and identified the non-pharmacological interventions from those results.

The comparison arm could have been placebo, an alternative intervention (pharmacological or non-pharmacological) or usual care, including no specific intervention for fatigue.

 

Types of outcome measures

 

Primary outcomes

The primary outcomes for this systematic review were self-reported fatigue scores using validated measures, and adverse events. Adverse events were recorded as reported in the studies on the basis of the Cochrane definition of "harms associated with healthcare interventions". Distinctions were made between an adverse event (unfavourable outcome occurring during, but not necessarily caused by, the intervention), an adverse effect (reasonable possibility of causal relation) and a side effect (any unintended effect) (Cochrane Handbook for Systematic Reviews of Interventions sections 14.1.2 and 14.3.1) (Higgins 2011).

 

Secondary outcomes

Secondary outcomes were pain, anxiety, depression, disability and tender or swollen joints.

 

Search methods for identification of studies

The search strategies were developed for MEDLINE in line with recommendations from the Cochrane Musculoskeletal Review Group and are shown in Appendix 1. The search strategies were applied to all databases (adapted appropriately to suit the database style): EMBASE (Appendix 2); CENTRAL (Appendix 3); CINAHL (Appendix 4); PsycINFO (Appendix 5); AMED (Appendix 6); Web of Science (Appendix 7); and Dissertation Abstracts International (Appendix 8).

 

Electronic searches

The following electronic databases were searched:

  • Cochrane Central Register of Controlled Trials (CENTRAL) (up to October 2012);

  • MEDLINE (1966 to October 2012);

  • EMBASE (1983 to October 2012);

  • AMED (1985 to October 2012);

  • CINAHL (1982 to October 2012);

  • PsycINFO (1974 to October 2012);

  • Social Science Citation Index (1990 to October 2012);

  • Web of Science (1990 to October 2012);

  • Dissertation Abstracts International (1871 to October 2012);

  • Current Controlled Trials Register (USA) (up to October 2012);

  • The National Research Register (NRR) Archive (UK) (up to October 2012);

  • The UKCRN Portfolio Database (UK) (up to October 2012).

 

Searching other resources

In addition, reference lists of studies identified for inclusion in the review as well as previous review papers were handsearched to find additional studies, as was the Arthritis Research Campaign (arc) Topical Review on Fatigue in Musculoskeletal Disease (Hewlett 2008). Relevant authors in the field were contacted to ask about unpublished research that was not detected by the search strategies.

 

Data collection and analysis

 

Inclusion criteria

Randomised controlled trials of adults with confirmed RA (Arnett 1988) where fatigue was included as a primary or secondary outcome measure (and not just an adverse effect), reported separately for RA patients.

 

Exclusion criteria

Studies that only investigated pharmacological interventions.

 

Selection of studies

Titles and abstracts were assessed for all records identified through the search strategies. Two review authors examined each citation and full papers were retrieved for all those appearing to meet the inclusion criteria. Full reports were also acquired where there was any uncertainty surrounding their inclusion or where abstracts were not available and it was not possible to exclude the trial based on title alone. Where there were disagreements regarding eligibility the full text was retrieved. All full text articles were screened for the inclusion and exclusion criteria by two independent review authors and any disagreements as to eligibility were resolved by discussion and the involvement of an arbiter where necessary.

 

Data extraction and management

For each publication, two review authors (papers allocated according to expertise) independently retrieved the following details, tabulated on a standardized form: intervention (including characteristics and duration); details of the participants' health status; assignment to study arm (including process used, concealment and comparability of arms); outcome measures; timing of measurements; adherence to intervention and control, sample size and statistical analysis methods (including intention to treat).

 

Assessment of risk of bias in included studies

For each paper, the two review authors independently assessed methodological quality using individual components of quality from tools such as that provided by the Cochrane Collaboration. Individual components rather than summary scores have been recommended (Khan 2001) in non-pharmacological trials where blinding of participants in a complex interaction has proved challenging, meaning that all such trials would score low for blinding. For such studies it was particularly important to assess whether obtaining outcome data was blinded.

The risk of bias of the included studies was also assessed by two independent review authors. As recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), the following methodological domains were assessed:

  1. sequence generation;
  2. allocation concealment;
  3. blinding of participants, personnel and outcome assessors;
  4. incomplete outcome data;
  5. selective outcome reporting; and
  6. other potential threats to validity (e.g. appropriate use of co-interventions).

Each of these criteria were explicitly judged and classified as: low risk of bias; high risk of bias or unclear (either insufficient information or uncertainty over the potential for bias).

Assessment of the power of the study to detect changes in RA fatigue was made by examining the power calculations reported in the studies. Assessment of the validity of the fatigue measure used was made using the methods of Hewlett 2007.

 

Measures of treatment effect

We expected a range of fatigue outcome measures to have been used in the identified studies therefore we planned a priori to use standardised mean differences. The central estimate (mean) and standard deviation were recorded. Where the standard deviations were not explicitly stated, they were calculated from the standard error, the different means and their respective confidence intervals or P values. Where adverse events were given as dichotomous data, they were reported as the proportion of patients experiencing the event in each arm and comparisons made.

 

Unit of analysis issues

We expected some non-pharmacological interventions to be delivered at the individual level, where the unit of analysis would be individual. Where interventions were delivered in groups, the group was the unit of analysis. However, group level interventions are often analysed and reported at an individual rather than group level, or without adjusting for group effect. Where these group data were not reported we contacted the authors for further information.

 

Dealing with missing data

Where change scores were not available these were sought from the authors. Where they were not available and the mean change could be calculated, standard deviations were imputed from baseline data using methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions (section 16.1.3.2) (Higgins 2011).

We intended a priori to carry out an intention-to-treat analysis in studies where patients allocated to the intervention arm were included regardless of whether or not they completed the follow-up. In these studies the assumption should have been made that patients who dropped out of the study had no changes in their outcomes, giving a conservative assessment of response to treatment. We requested further details from authors in cases where published data were incomplete.

 

Assessment of heterogeneity

Where appropriate, heterogeneity of the data was formally assessed using the I2 statistic (Higgins 2003). A value greater than 50% may represent substantial heterogeneity. Where substantial heterogeneity was detected, and there were sufficient studies available, subgroup analyses was proposed in an attempt to explain the heterogeneity.

 

Assessment of reporting biases

A funnel plot was used to assess the possibility of publication bias.

 

Data synthesis

Included studies were graded using the GRADE approach (Schünemann 2008), which employs the following rating system: randomised trials (high), downgraded randomised trials (moderate), double-downgraded randomised trials (low) and triple-downgraded randomised trials (very low). The quality ratings may be decreased by:

  1. limitations in the design and implementation of available studies suggesting high likelihood of bias;
  2. indirectness of evidence (indirect population, intervention, control, outcomes);
  3. unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses);
  4. imprecision of results (wide confidence intervals); or
  5. high probability of publication bias.

We expected a mixture of changes from baseline and absolute study arm differences across a variety of measures of RA fatigue. We also expected some variation in methods of analysis, including the absolute difference compared between study arms, and baseline-adjusted differences between arms. We followed the Cochrane Handbook for Systematic Reviews of Interventions guidelines (Higgins 2011) in section 9.4.5.2 in deciding which group of studies could be included in any meta-analysis. We imputed standard deviations (SD) where necessary according to section 16.1.3.

In studies with multiple intervention arms the number of participants included in the control arm was divided by the number of intervention arms to avoid double counting. Where more than one fatigue outcome existed in a single study, visual analogue scale (VAS) data, if present, were selected for inclusion in the meta-analysis. Where VAS data were not available data for the SF-36 vitality scale were utilised. For any remaining studies with multiple fatigue outcome measures that did not include the VAS or SF36, the measure selected for use in the review was based upon the findings of a previous critical review of fatigue scales in RA (Hewlett 2007).

Where there was no heterogeneity a fixed-effect model was used, and where there was heterogeneity a random-effects model was proposed. When the outcome used or the number, quality or heterogeneity of existing trials contraindicated meta-analysis, each study was reported and discussed individually using effect sizes for fatigue difference (differences divided by the SD) using Cohen’s statistic (0.2 to 0.5 = small effect, 0.5 to 0.8 = moderate, > 0.8 = large effect) (Cohen 1998).

 

Subgroup analysis and investigation of heterogeneity

Where sufficient studies were available and the data were heterogenous, meta-analyses were carried out for studies using similar intervention approaches, for example exercise, self-management education programmes, or cognitive-behavioural therapy. A priori, the categories of physical activity and psychosocial interventions were expected to emerge from the available data. A conversion proposed by Chinn (Chinn 2000) was used to convert standardised mean differences (SMDs) into odds ratios (OR) with the control event rate estimated from Hewlett 2011c.

 

Sensitivity analysis

The following sensitivity analyses were planned a priori in order to explore differences in effect size and to assess whether the conclusions were robust to the decision-making process:

  1. the effect of risk of bias in included studies, defined as adequate allocation concealment and blinding of outcome assessors; and
  2. the effect of imputing missing data or transforming variables.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies

 

Results of the search

See: Figure 1

 FigureFigure 1. Study flow diagram.

Through a comprehensive literature search, including screening of titles and abstracts (where available), attempts were made to retrieve 60 full text references for further evaluation. From these, 37 publications were excluded and 23 identified as appropriate for inclusion in the current review. Screening of reference lists led to the retrieval of eight further full text studies. One of the eight was identified as appropriate for inclusion resulting in 24 studies in total. The 24 publications reported separate trials with one study (Giraudet-Le-Quintrec 2007) providing additional data in a separate report.

 

Included studies

The final selection, based on consensus, resulted in 24 trials being identified for inclusion in the review. The studies were published between 1985 and 2012. Three of the included studies (Danoff-Burg 2006 - I; Neuberger 2007 - I; Riemsma 2003 - I) incorporated three separate study arms and were therefore entered twice for the purpose of statistical analysis.

 

Participants

Overall, data were available for 2882 participants with RA. The number of participants completing the studies ranged from 11 (Otter 2010) to 714 (Huffstutter 2007).

The mean age of participants fell mainly within the fifth decade with five studies reporting a mean age in the mid to late 40s and two reporting the mean age to be in the 60s. One study specifically recruited housebound patients over the age of 50 years and subsequently reported a mean age of 77.7 years (Laforest 2008), whereas another study only recruited patients aged 18 to 35 years and reported a mean age of 28.3 years (Evans 2012). Two studies did not report the gender of participants (Das Gupta 2009; Otter 2010). Twenty of the remaining 23 studies recruited both males and females with 19 of these reporting a higher percentage of females and one not providing these data (Burgos 2009). However, three of the studies provided gender data for the entire population recruited with no specific gender data reported for participants with RA (Danoff-Burg 2006 - I; Lorig 2005; Zangi 2012). Two studies recruited females only (Evans 2012; Harkcom 1985).

Seventeen studies included participants with RA diagnosed according to the 1987 ACR criteria, four studies relied upon verification of RA by a clinician (Hammond 2008; Laforest 2008; Lorig 2005; Otter 2010), one study included participants based upon the American Rheumatism Association (ARA) 1958 guidelines (Harkcom 1985). The remaining two studies either did not clarify the method of diagnosing people with RA (Danoff-Burg 2006 - I) or did not employ a consistent approach to diagnosis (Lorig 2008).

Nine studies reported that participants' mean duration of disease was greater than 12 years (Hammond 2008; Harkcom 1985; Hewlett 2011; Huffstutter 2007; Lumley 2011-I; Otter 2010; Skoldstam 2003; Wang 2008; Zangi 2012). Three studies reported the mean duration of disease as less than three years (Bilberg 2005; Danoff-Burg 2006 - I; Hakkinen 2003) and a further four studies did not report disease duration for the participants (Das Gupta 2009; Laforest 2008; Lorig 2005; Lorig 2008).

 

Interventions

See  Table 1

Six of the studies investigated physical activity (Bilberg 2005; Evans 2012; Hakkinen 2003; Harkcom 1985; Neuberger 2007 - I; Wang 2008). The physical activity interventions included pool-based therapy (Bilberg 2005), yoga (Evans 2012), dynamic strength training (Hakkinen 2003), stationary cycling (Harkcom 1985), low impact aerobics (Neuberger 2007 - I) and Tai Chi (Wang 2008). Thirteen studies were broadly categorised as investigating psychosocial interventions (Danoff-Burg 2006 - I; Evers 2002; Furst 1987; Giraudet-Le-Quintrec 2007; Hammond 2008; Helliwell 1999; Hewlett 2011; Laforest 2008; Lorig 2005; Lorig 2008; Lumley 2011-I; Riemsma 2003 - I; Zangi 2012). These interventions included benefit finding (Danoff-Burg 2006 - I), expressive writing (Danoff-Burg 2006 - I; Lumley 2011-I), cognitive behavioural therapy (Evers 2002; Hewlett 2011; Lumley 2011-I), mindfulness (Zangi 2012), lifestyle management (Hammond 2008), energy conservation (Furst 1987), self-management (Laforest 2008; Lorig 2005; Lorig 2008) and group education (Giraudet-Le-Quintrec 2007; Helliwell 1999; Riemsma 2003 - I). The remaining five studies investigated a range of other non-pharmacological interventions (Burgos 2009; Das Gupta 2009; Huffstutter 2007; Otter 2010; Skoldstam 2003).

 

Outcome measures

A wide range of self-report measures were used to assess fatigue, with six of the 24 studies including two different self-report fatigue measures (Danoff-Burg 2006 - I; Evans 2012; Furst 1987; Hewlett 2011; Neuberger 2007 - I; Wang 2008). Thirteen studies used variations of a numerical rating scale (NRS) or visual analogue scale (VAS) to measure fatigue or tiredness (Danoff-Burg 2006 - I; Furst 1987; Hakkinen 2003; Hammond 2008; Hewlett 2011; Huffstutter 2007; Laforest 2008; Lorig 2005; Lorig 2008; Lumley 2011-I; Riemsma 2003 - I; Wang 2008; Zangi 2012). The majority of these studies used the VAS or NRS to measure average fatigue during a specific time period, for example the past seven days, although two studies monitored fatigue levels during a specific activity (Furst 1987; Hakkinen 2003). Seven studies used the Short Form 36 (SF-36) vitality subscale to measure fatigue (Bilberg 2005; Burgos 2009; Das Gupta 2009; Evans 2012; Helliwell 1999; Skoldstam 2003; Wang 2008). Three studies used the Multidimensional Assessment of Fatigue (MAF) (Hewlett 2011; Neuberger 2007 - I; Otter 2010), two studies used the Profile of Mood States (POMS) vigour subscale to monitor fatigue levels (Danoff-Burg 2006 - I; Neuberger 2007 - I), two studies used the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) (Evans 2012; Giraudet-Le-Quintrec 2007), and one used the Checklist Individual Strength (CIS) (Evers 2002). The final study asked participants to rate their perception of change in fatigue from baseline using a four point Likert scale (Harkcom 1985).

Fatigue was identified as the single primary outcome in one study (Otter 2010) and fatigue impact was the single primary outcome in another study (Hewlett 2011). Burgos 2009 included tiredness as one of their three primary outcomes. Evers 2002 identified physical, psychological and social functioning as their primary outcomes, where physical functioning encompassed fatigue. None of the remaining studies reported fatigue as a primary outcome although six studies did not identify the primary outcome (Danoff-Burg 2006 - I; Das Gupta 2009; Evans 2012; Furst 1987; Harkcom 1985; Neuberger 2007 - I).

 

Excluded studies

The 37 publications that were subsequently excluded did not meet the review inclusion criteria for the following reasons: 16 were not RCTs, 13 did not report fatigue as an outcome measure, seven did not report fatigue data separately for RA patients, and one paper was unobtainable. Details of the excluded studies can be found in the Characteristics of excluded studies table. A further two studies are awaiting classification, with one of the studies requiring translation (Wiesenauer 1991) and for the remaining study further data are needed before a decision can be made regarding inclusion (Berbert 2005). The additional seven studies identified through snowballing, which were retrieved in full and subsequently excluded, did not include fatigue as an outcome.

 

Risk of bias in included studies

Two authors independently reviewed all included studies for ‘risk of bias’ (Figure 2; Figure 3). Any discrepancies were easily resolved through group discussion. Eight items were assessed to determine ‘risk of bias’ although it should be noted that three of the eight items related to blinding (participants, personnel and outcome assessors). Only published material was used to assess risk of bias and authors were not contacted to seek clarification. Therefore, a number of items remained unclear and although it could not be stated that the quality criteria had been met it equally could not be stated that they had not been met.

 FigureFigure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
 FigureFigure 3. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Overall, two studies each met seven (Burgos 2009; Giraudet-Le-Quintrec 2007), and six (Hammond 2008; Lorig 2005) of the eight criteria. Five studies met five criteria (Danoff-Burg 2006 - I; Helliwell 1999; Hewlett 2011; Wang 2008; Zangi 2012) and a further three met four criteria (Bilberg 2005; Evers 2002; Otter 2010). Six studies only met three criteria (Evans 2012; Hakkinen 2003; Laforest 2008; Lorig 2008; Lumley 2011-I; Neuberger 2007 - I), two met two criteria (Furst 1987; Skoldstam 2003), two met one criterion (Harkcom 1985; Riemsma 2003 - I) and the final two studies did not meet any of the criteria assessed (Das Gupta 2009; Huffstutter 2007).

Based upon intervention category, the studies investigating physical activity provided moderate quality evidence whereas the studies investigating psychosocial interventions provided low quality evidence. The remaining studies, categorised as 'other' interventions, were assessed as providing low quality evidence except for the study investigating a Mediterranean diet that was assessed as providing moderate quality evidence.

 

Allocation

There was poor reporting of the procedures used to conceal trial arm allocation with 14 of the 24 studies providing insufficient information to judge this criterion accurately (Bilberg 2005; Das Gupta 2009; Evans 2012; Evers 2002; Hakkinen 2003; Huffstutter 2007; Laforest 2008; Lorig 2005; Lorig 2008; Lumley 2011-I; Neuberger 2007 - I; Otter 2010; Riemsma 2003 - I; Skoldstam 2003). Further to this, nine of the studies did not report sequence generation in sufficient detail (Danoff-Burg 2006 - I; Das Gupta 2009; Evans 2012; Hakkinen 2003; Harkcom 1985; Huffstutter 2007; Lorig 2008; Otter 2010; Riemsma 2003 - I). The remaining studies described a variety of acceptable methods for sequence generation and allocation concealment. In the majority of the latter studies the methods for developing an 'a priori' list for randomisation were described and pre-prepared sealed, opaque, sequentially numbered envelopes were the favoured method of allocation concealment.

Based upon intervention category, three of the six physical activity intervention studies identified appropriate random sequence allocation (Bilberg 2005; Neuberger 2007 - I; Wang 2008) and two appropriately concealed allocation (Harkcom 1985; Wang 2008). Ten of the 13 psychosocial intervention studies identified appropriate random sequence allocation (Evers 2002; Furst 1987; Giraudet-Le-Quintrec 2007; Hammond 2008; Helliwell 1999; Hewlett 2011; Laforest 2008; Lorig 2005; Lumley 2011-I; Zangi 2012) and seven appropriately concealed allocation (Danoff-Burg 2006 - I; Furst 1987; Giraudet-Le-Quintrec 2007; Hammond 2008; Helliwell 1999; Hewlett 2011; Zangi 2012). For the remaining five studies only two appropriately identified random sequence allocation (Burgos 2009; Skoldstam 2003) and only one detailed allocation concealment adequately (Burgos 2009).

 

Blinding

Blinding was a limitation for the large majority of the studies. Nine studies failed to blind participants (Das Gupta 2009; Hammond 2008; Hewlett 2011; Huffstutter 2007; Laforest 2008; Lorig 2008; Neuberger 2007 - I; Otter 2010; Zangi 2012) and a further 10 studies failed to adequately report blinding of participants (Bilberg 2005; Evers 2002; Furst 1987; Hakkinen 2003; Harkcom 1985; Helliwell 1999; Lumley 2011-I; Riemsma 2003 - I; Skoldstam 2003; Wang 2008). Fifteen studies did not blind the study personnel (Danoff-Burg 2006 - I; Das Gupta 2009; Evans 2012; Evers 2002; Giraudet-Le-Quintrec 2007; Hammond 2008; Harkcom 1985; Helliwell 1999; Hewlett 2011; Huffstutter 2007; Laforest 2008; Lorig 2008; Neuberger 2007 - I; Skoldstam 2003; Zangi 2012) and a further six failed to report the procedure for this (Bilberg 2005; Furst 1987; Hakkinen 2003; Lumley 2011-I; Riemsma 2003 - I; Wang 2008). Two studies did not blind the outcome assessors (Huffstutter 2007; Skoldstam 2003) and 10 studies did not report this adequately (Burgos 2009; Das Gupta 2009; Evans 2012; Evers 2002; Furst 1987; Hakkinen 2003; Harkcom 1985; Lorig 2008; Lumley 2011-I; Riemsma 2003 - I). Several studies acknowledged the difficulties associated with blinding participants to non-pharmacological interventions and made attempts to blind the outcome assessor by using personnel not otherwise involved in the study. However, several of the studies used subjectively-reported outcomes with unblinded participants. In this situation the use of a blinded outcome assessor would not have changed the risk of bias.

All physical activity intervention studies and those categorised as 'other' either did not blind adequately or provided insufficient information. Only one of the psychosocial intervention studies provided adequate blinding (Lorig 2005).

 

Incomplete outcome data

The majority of studies provided complete outcome data with only four studies assessed as providing incomplete data (Das Gupta 2009; Furst 1987; Harkcom 1985; Huffstutter 2007) and a further four studies judged to be unclear (Danoff-Burg 2006 - I; Laforest 2008; Riemsma 2003 - I; Skoldstam 2003). The four studies that were considered to have incomplete outcome data all failed to explain how missing data were handled. The reasons for participants leaving the study early were also omitted in some studies. The studies that met this criterion mainly performed analysis on an intention-to-treat basis although the methods used varied.

Five of the six physical activity intervention studies were considered to be at low risk of incomplete outcome data reporting, the remaining study was considered to be at high risk (Harkcom 1985). For the psychosocial intervention studies, nine were considered to be at low risk, one at high risk (Furst 1987) and three were unclear for incomplete outcome data reporting (Danoff-Burg 2006 - I; Laforest 2008; Riemsma 2003 - I). For the five remaining studies, two were at low risk, one was unclear (Skoldstam 2003) and two at high risk (Das Gupta 2009; Huffstutter 2007).

 

Selective reporting

The majority of studies were judged to be free from selective reporting with only four studies considered to have selectively reported the findings (Das Gupta 2009; Furst 1987; Harkcom 1985; Neuberger 2007 - I) and two studies were judged to be unclear (Huffstutter 2007; Lumley 2011-I). One study reported the findings of an outcome that was not included within the methodology (Das Gupta 2009) and a further study combined the outcomes of different intervention groups resulting in insufficient detail (Harkcom 1985). Three studies did not report the results for all the outcomes listed in the methodology although the authors for one of these studies subsequently provided these data upon request.

For the physical activity intervention studies, two were considered to be at high risk of selective reporting (Harkcom 1985; Neuberger 2007 - I) and the remaining four at low risk. For the psychosocial intervention studies, 11 were considered to be at low risk of selective reporting, one was unclear (Lumley 2011-I) with the one remaining study considered to be at high risk (Furst 1987). For the remaining five studies, three were at low risk, one unclear (Huffstutter 2007) and one at high risk (Das Gupta 2009) of selective reporting.

 

Other potential sources of bias

Thirteen of the 24 studies were considered to be at high risk of bias for ‘other’ reasons (Bilberg 2005; Das Gupta 2009; Evans 2012; Furst 1987; Harkcom 1985; Helliwell 1999; Laforest 2008; Lorig 2008; Neuberger 2007 - II; Otter 2010; Skoldstam 2003; Wang 2008; Zangi 2012). The main reasons identified were study arms being unbalanced at baseline, a risk of contamination between the arms, payment of participants in one arm of the study, and control arm participants advised that they would be entitled to receive the active intervention at the end of the study period.

For the physical activity intervention studies, five were considered to be at high risk of other bias (Bilberg 2005; Evans 2012; Harkcom 1985; Neuberger 2007 - I; Wang 2008) and the remaining study at low risk. For the psychosocial intervention studies, seven were considered to be at low risk of other bias, one unclear (Riemsma 2003 - I) and five at high risk (Furst 1987; Helliwell 1999; Laforest 2008; Lorig 2008; Zangi 2012). For the remaining five studies, three were at high risk of selective reporting (Das Gupta 2009; Otter 2010; Skoldstam 2003) and one was unclear (Huffstutter 2007).

 

Effects of interventions

See:  Summary of findings for the main comparison Non-pharmacological interventions for rheumatoid arthritis

 
Fatigue

It was not considered appropriate to combine the data for all the studies included within the review due to the heterogeneity in relation to the interventions under investigation. Data were therefore combined for subgroups, in separate meta-analyses, for studies investigating physical activity interventions and psychosocial interventions. The remaining five studies did not fit within these subgroups and were therefore reported narratively.

 
Physical activity interventions: effect on fatigue

A meta-analysis was used to combine the mean change scores from pre- to post-test for the six studies investigating physical activity interventions (see  Analysis 1.1). There were a maximum of seven comparisons possible due to the inclusion of two interventions in one study (Neuberger 2007 - I). However, mean change data for fatigue were not available for one of the seven comparisons (Harkcom 1985). The remaining six comparisons provided data for 219 participants who received a physical activity intervention and 152 participants in the control arm. Data were combined using a random-effects model meta-analysis due to the heterogeneity within the outcome measures used to assess fatigue. At the end of the intervention period physical activity was statistically significantly more effective than the control (SMD -0.36, 95% CI -0.62 to -0.10; number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 4 to 26), demonstrating a small effect.

The quality of the evidence was graded as moderate using the GRADE approach (see  Summary of findings for the main comparison). The funnel plot did not demonstrate obvious publication bias for the physical activity interventions although it cannot be ruled out (see Figure 4).

 FigureFigure 4. Funnel plot of comparison: 1 Physical activity versus control, outcome: 1.1 Fatigue.

 
Psychosocial interventions: effect on fatigue

A meta-analysis was used to combine the mean change scores from pre- to post-test for the 13 studies investigating psychosocial interventions (see  Analysis 2.1). There were a maximum of 16 comparisons possible due to the inclusion of two intervention arms in three studies (Danoff-Burg 2006 - I; Lumley 2011-I; Riemsma 2003). However, mean change data for fatigue were not available for one of the comparisons (Furst 1987). The remaining 15 comparisons provided data for 843 participants who received a psychosocial intervention and 713 participants in the control arm. Data were combined using a random-effects model meta-analysis due to the heterogeneity within the outcome measures used to assess fatigue. At the end of the intervention period psychosocial interventions were statistically significantly more effective than the controls (SMD -0.24, 95% CI -0.40 to -0.07; NNTB 9, 95% CI 6 to 33), demonstrating a small effect.

The quality of the evidence was graded as low using the GRADE approach (see  Summary of findings for the main comparison).The funnel plot did not demonstrate obvious publication bias for the psychosocial interventions although it cannot be ruled out (see Figure 5).

 FigureFigure 5. Funnel plot of comparison: 2 Psychosocial versus control, outcome: 2.1 Fatigue.

 
Other interventions: effect on fatigue

The remaining five studies investigated diverse non-pharmacological interventions and were therefore not appropriate for combining within a meta-analysis. In brief, Skoldstam 2003 investigated Mediterranean diet compared to an ordinary Western diet. The Mediterranean diet arm demonstrated statistically significant improvement in the SF-36 vitality score at the end of the intervention (12 weeks) whereas no statistically significant change was shown in the Western diet arm; between arm comparisons were not reported (see  Analysis 3.1). Burgos 2009 investigated the herbal medicine Andrographis paniculata compared to a placebo. No statistically significant differences were reported between arms for tiredness measured on a VAS (see  Analysis 4.1). Das Gupta 2009 investigated omega-3 fatty acid supplementation in patients receiving indomethacin. Both study arms demonstrated statistically significant improvements in SF-36 vitality between baseline and at 12 weeks, with between arm comparisons not reported (see  Analysis 5.1). Huffstutter 2007 investigated the use of a data capture system to provide patients with graphical summarised health information in comparison to a usual care control arm. Statistical analysis of VAS fatigue data was not reported. Additional data provided by the authors demonstrated small improvements in VAS fatigue from baseline to follow-up in both arms (see  Analysis 6.1). Finally, Otter 2010 investigated reflexology compared to a non-specific foot massage with fatigue as the primary outcome. The authors reported a greater mean reduction in fatigue in the reflexology arm compared to the control arm but did not perform inferential statistics on the data due to the small number of participants (see  Analysis 7.1).

 
Pain

Two of the 24 studies did not include pain as an outcome (Bilberg 2005; Giraudet-Le-Quintrec 2007). Fourteen of the studies that measured pain used variations of a VAS or NRS (Burgos 2009; Danoff-Burg 2006 - I; Das Gupta 2009; Furst 1987; Hakkinen 2003; Hammond 2008; Hewlett 2011; Huffstutter 2007; Laforest 2008; Lorig 2005; Lorig 2008; Skoldstam 2003; Wang 2008; Zangi 2012). Other measures used were a Likert scale (Harkcom 1985); the short-form McGill Pain Questionnaire (Neuberger 2007 - I), the pain subscale of the Dutch AIMS2 (Riemsma 2003 - I; Lumley 2011-I); the pain scale of the Impact of Rheumatic Diseases on General Health and Lifestyle (IRGL) (Evers 2002), the Pain Disability Index (Evans 2012), the Bodily Pain subscale of the SF-36 (Helliwell 1999) and the Manchester Foot Pain Disability Questionnaire (Otter 2010).

For the studies investigating physical activity interventions, Harkcom 1985 reported improvements in pain over time for the exercise programme in comparison to home-based exercise or a control arm. However, statistical analysis was not reported separately for the pain data. Hakkinen 2003 reported a statistically significant improvement in average pain intensity at 24 months in the dynamic strength training arm compared to a control arm that carried out range of motion and stretching exercises. The remaining physical activity intervention studies that recorded pain as an outcome reported no statistically significant effects (Evans 2012; Wang 2008).

Six of the psychosocial intervention studies that measured pain as an outcome did not report separate RA data (Danoff-Burg 2006 - I; Hammond 2008; Laforest 2008; Lorig 2005; Lorig 2008; Zangi 2012). Four of the studies reported no statistically significant effects either over time or between arms (Evers 2002; Helliwell 1999; Hewlett 2011; Riemsma 2003 - I). One study reported statistically significant improvement in pain over time but no statistically significant differences between the intervention and control arms (Furst 1987). The final study reported a statistically significant improvement in pain following a coping skills training intervention compared to the control education arm but no statistically significant difference between the written emotional disclosure arm and control writing arm (Lumley 2011-I).

For the 'other' categorised interventions, Otter 2010 reported a decrease in pain for both study arms but no inferential statistics were carried out. One study reported no statistically significant effects either over time or between arms (Burgos 2009). Two of the studies reported statistically significant improvement in pain over time but no statistically significant differences between the intervention and control arms (Das Gupta 2009; Huffstutter 2007). Finally, Skoldstam 2003 reported a statistically significant reduction in pain following a 12-week Mediterranean diet intervention in comparison to a usual diet.

 
Anxiety

Only seven of the 24 studies included anxiety as an outcome (Danoff-Burg 2006 - I; Evans 2012; Evers 2002; Giraudet-Le-Quintrec 2007; Hewlett 2011; Lumley 2011-I; Zangi 2012) with a range of different assessment methods. Six of the seven studies were categorised as psychosocial interventions. One of these did not provide data specific to the RA participants (Zangi 2012) and a further study did not report the findings for anxiety within the results (Lumley 2011-I). Danoff-Burg 2006 - I only measured anxiety at baseline but interestingly reported that higher levels of anxiety were statistically significantly associated with greater fatigue at both one and three months (combined data for participants with RA and systemic lupus erythematosus (SLE)). Giraudet-Le-Quintrec 2007 and Hewlett 2011 reported no statistically significant changes in anxiety due to their psychosocial interventions. Evers 2002 also reported no condition by time interaction for anxiety in their investigation of a cognitive behavioural therapy programme. The final study that investigated the effect of Ivengar yoga reported no statistically significant effect for anxiety (Evans 2012).

 
Depression

Ten studies included depression as an outcome (Danoff-Burg 2006 - I; Evans 2012; Evers 2002; Giraudet-Le-Quintrec 2007; Hewlett 2011; Laforest 2008; Lumley 2011-I; Neuberger 2007 - I; Wang 2008; Zangi 2012) with the Centre for Epidemiological Studies depression scale (CES-D) being used in four of the 10 studies. Two of the studies did not provide full outcome data or an analysis for the depression data (Laforest 2008; Lumley 2011-I) and a further two studies only provided combined data for participants with inflammatory arthritis (Danoff-Burg 2006 - I; Zangi 2012).

For physical activity interventions, Neuberger 2007 - I reported an overall positive effect for depression but results for univariate analysis were not reported. Wang 2008 reported a decrease in depression immediately following a 12-week Tai Chi programme with a corresponding increase in depression in the control arm and an overall statistically significant between arm effect. Evans 2012 reported that there was no statistically significant effect due to an Ivengar yoga intervention compared to a control arm.

For psychosocial interventions, one study reported no statistically significant effects in relation to depression (Giraudet-Le-Quintrec 2007). Evers 2002 and Hewlett 2011 reported that depression was statistically significantly reduced following a cognitive behavioural therapy intervention in comparison to the control arms.

 
Disability

Eighteen of the 24 studies included disability as an outcome measure. Sixteen of the 18 studies used the Health Assessment Questionnaire (HAQ) or a modified version of the HAQ to assess disability. The remaining studies used the Mobility and Self-care scales of the Impact of Rheumatic Diseases on General Health and Lifestyle to assess disability (Evers 2002) or the Arthritis Impact Measurement Scales 2 (AIMS2) physical disability subscale Lumley 2011-I).

Four of the six studies categorised as physical activity studies included disability as an outcome. The studies investigating hydrotherapy (Bilberg 2005) and Tai Chi (Wang 2008) demonstrated statistically significant improvements in the intervention arm compared to the control arm between baseline and follow-up. The studies investigating strength training (Hakkinen 2003) and Ivengar yoga (Evans 2012) did not demonstrate a statistically significant difference between study arms.

Ten of the 13 studies investigating psychosocial interventions included disability as an outcome measure although four of these did not provide separate RA data (Danoff-Burg 2006 - I; Hammond 2008; Lorig 2005; Lorig 2008). Four of the six remaining studies reported no statistically significant time by arm interaction (Evers 2002; Giraudet-Le-Quintrec 2007; Helliwell 1999; Lumley 2011-I). One study (Furst 1987) did not carry out statistical analysis of the disability data but reported that there were no differences between the arms over time. The final study reported statistically significantly better disability in the trial arm that had received cognitive behavioural therapy compared to the control arm at the primary endpoint (Hewlett 2011).

In the remaining studies, Burgos 2009 reported a statistically significant improvement in disability over time with no statistically significant differences between the arm receiving andrographolides and the placebo arm. Skoldstam 2003 reported a statistically significant difference between arms from baseline to the 12-week follow-up. Findings were in favour of the intervention arm receiving the Mediterranean diet. Finally, Das Gupta 2009 and Huffstutter 2007 did not present the findings for disability despite including the HAQ as an outcome measure within the methods.

 
Tender and swollen joints

Several studies included the Disease Activity Score (DAS28) as an outcome. This outcome incorporates an assessment of the number of tender and swollen joints. However, the separate scores were often not reported. Studies were only reported here that provided separate evaluation of tender or swollen joints, or both, or results for the Ritchie Articular Index (a graded assessment of 26 joint regions to assess tenderness plus a 44 joint count to assess swelling). Ten of the 19 studies met these criteria.

Four of the studies investigating physical activity interventions reported findings for tender and swollen joints. Harkcom 1985 reported statistically significant reductions in joint counts (combined tenderness and swelling scores) in all three cycle ergometry intervention arms between baseline and post-treatment, with a statistically non-significant reduction in the control arm. However, statistical analysis was not reported for between arm comparisons. Hakkinen 2003 reported improvements in the Ritchie Articular Index (RAI) in both the strength training arm and the control arm with no statistically significant differences between arms. Neuberger 2007 - I reported no statistically significant differences in total joint count between the low impact aerobic exercise arms and the control arm. Similarly, Wang 2008 reported no statistically significant differences between the hydrotherapy arm and control arm in relation to joint pain, joint swelling or RAI values.

Only two of the studies investigating psychosocial interventions measured and reported tender and swollen joint counts. Furst 1987 reported a statistically non-significant increase in RAI (worse) in both the energy conservation arm and the control. Between arm statistical analysis was not however reported. Helliwell 1999 reported no statistically significant difference in RAI between patients receiving group education and a control.

In the remaining studies, Burgos 2009 reported no statistically significant difference in tender joint counts, swollen joint counts, grade of swollen joints or grade of tender joints between the herbal medicine and control arm from baseline to follow-up. Das Gupta 2009 reported that tender and swollen joint counts decreased statistically significantly in the arm receiving omega-3 fatty acids as well as the placebo control arm. Between arm statistical analysis was not reported. Huffstutter 2007 reported a statistically significant improvement in mean painful joint count in the arm receiving health tracker data compared to a statistically non-significant improvement in the control arm. Again, between trial arm statistical analysis was not reported. Finally, Skoldstam 2003 demonstrated a statistically significant decrease in swollen joint count over time in the trial arm receiving a Mediterranean diet compared to the control arm. There was no corresponding difference in tender joint counts. 

 
Adverse events

No adverse events were reported in 21 of the 24 studies. However, in some cases it was not clear if this was due to the absence of any adverse events or poor reporting. The remaining three studies reported adverse events (Burgos 2009; Huffstutter 2007; Skoldstam 2003) but none were serious and there was no clear difference in the incidence or severity of the adverse events between the intervention and control arms. No adverse effects or side effects were reported in any of the studies.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Summary of main results

The aim of this review was to provide an overview of the benefits and harms of non-pharmacological interventions for fatigue in people with RA. The review revealed 24 studies in which a non-pharmacological intervention had been investigated in an RCT design and fatigue had been included as an outcome measure. The interventions were heterogenous with six studies investigating a form of physical activity, 13 investigating a psychosocial intervention, and the five remaining studies investigating a herbal medicine, Mediterranean diet, omega-3 fatty acid supplementation, reflexology and the provision of health tracker information. The quality of the evidence varied from low to moderate.

 

Overall completeness and applicability of evidence

One study identified fatigue as the single primary outcome and a further study identified fatigue impact as a the primary outcome. Tiredness was also identified as the primary outcome in one study and a further study included fatigue as one of several primary outcomes. As a consequence the primary purpose of the interventions for the majority of studies was not fatigue reduction and there was little or no apparent consideration of fatigue mechanisms in the design of the interventions. Future research needs to focus specifically upon fatigue to determine the most effective methods for management. Interventions should also be designed with consideration given to potential causal pathways and mechanisms of fatigue. The lack of specific focus on fatigue within the included studies may have resulted in an underestimation of the effectiveness of non-pharmacological interventions. It should be noted that only one of the studies identified the presence of fatigue as a specific inclusion criteria. It is highly likely that for some participants fatigue was not a clinically significant problem thus reducing the potential for improvement. Future research therefore needs to be undertaken with fatigued participants. Further to this, only one of the included studies was specifically powered to detect a change in fatigue, although it is likely that some studies did have sufficient numbers for this purpose. It is possible that fatigue has been included as a secondary outcome in additional studies and not reported where no effect was detected. This potential for selective reporting may have led to an exaggeration in the benefits of the included interventions upon fatigue. The absence of reporting of adverse events or side effects does not allow the important benefits to be balanced against potential harms.

 

Quality of the evidence

Fatigue outcome measures need to be standardised in future RA research. Although 13 of the included studies used a NRS or VAS there was no standardisation of the root question or anchor statements. A range of other multi-dimensional fatigue measures were used that have not been validated in full for use in RA, for example, the FACIT-F, MAF and CIS (Hewlett 2011b). The use of the SF-36 may also be questionable as vitality may not be at the opposite end of the spectrum to fatigue. Consistent use of outcomes would simplify pooling of data and allow comparison between interventions.

Due to inadequate reporting in the majority of included studies it was often not possible to determine whether the quality criteria had been met. This resulted in a large number of items being scored as unclear rather than met or not met. Blinding was highlighted as a limitation in the majority of the included studies. There are inherent difficulties in blinding non-pharmacological interventions, although it is not impossible and future research needs to make efforts to address this to limit risk of bias.

 

Potential biases in the review process

The inclusion criteria for this review were intentionally broad to capture all non-pharmacological interventions that may have potential to reduce fatigue in patients with RA. Unsurprisingly this resulted in heterogeneity between the interventions under investigation. For the purpose of data pooling an artificial cut off was created between psychosocial and physical activity interventions. In general it was clear where the main component of the intervention was physical activity or psychosocial, however, there was also some overlap in a few studies. In the future, assuming that the number and quality of studies increases, it may be possible to determine a priori meta-analysis with more homogenous interventions. It may also be possible to perform meta-analysis upon intervention subgroups; for example, physical activity interventions may be classified as primarily aerobic training or resistance training. This would help to create consensus in relation to optimal management of fatigue and better informed clinical guidelines.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

 

Implications for practice

There is some evidence that physical activity interventions and psychosocial interventions may help to reduce fatigue in RA. However, the optimal parameters and components of these interventions are not yet established.

 
Implications for research

High quality randomised controlled trials with cost effectiveness analysis are necessary to determine the optimal non-pharmacological management of fatigue in RA. The initial priority should be to identify the optimal physical activity and psychosocial interventions with fatigue as the primary outcome. Further to this, it is essential that trials are reported in line with the CONSORT statement. In particular, adverse events and side effects need to be incorporated in future publications even when none occur.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Louise Falzon, Trials Search Coordinator of the Cochrane Musculoskeletal Group, for providing assistance with the search strategy.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
Download statistical data

 
Comparison 1. Physical activity versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Fatigue6371Std. Mean Difference (IV, Random, 95% CI)-0.36 [-0.62, -0.10]

 
Comparison 2. Psychosocial versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Fatigue151556Std. Mean Difference (IV, Random, 95% CI)-0.24 [-0.40, -0.07]

 
Comparison 3. Mediterranean diet versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Fatigue151Std. Mean Difference (IV, Random, 95% CI)0.37 [-0.18, 0.93]

 
Comparison 4. Andrographis paniculata versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Fatigue158Std. Mean Difference (IV, Random, 95% CI)-0.25 [-0.77, 0.27]

 
Comparison 5. Omega-3 fatty acid versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Fatigue181Std. Mean Difference (IV, Random, 95% CI)0.93 [0.47, 1.39]

 
Comparison 6. Data tracker versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Fatigue1714Std. Mean Difference (IV, Random, 95% CI)0.06 [-0.10, 0.21]

 
Comparison 7. Reflexology versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Fatigue111Std. Mean Difference (IV, Random, 95% CI)-1.24 [-2.59, 0.11]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Appendix 1. MEDLINE search strategy

1. exp arthritis, rheumatoid/

2. ((rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or rheumat$ or reumat$ or revmarthrit$) adj3 (arthrit$ or artrit$ or diseas$ or condition$ or nodule$)).tw.

3. 1 or 2

4. exp Fatigue/

5. fatigue$.tw.

6. (tired$ or weary or weariness or exhaustion or exhausted).tw.

7. ((astenia or asthenic) and syndrome).tw.

8. ((lack or loss or lost) adj3 (energy or vigo?r)).tw.

9. (apath$ or lassitude or weak$ or letharg$).tw.

10. (feel$ adj3 (drained or sleep$ or sluggish)).tw.

11. vitality.tw.

12. or/4-11

13. randomized controlled trial.pt.

14. controlled clinical trial.pt.

15. randomized.ab.

16. placebo.ab.

17. drug therapy.fs.

18. randomly.ab.

19. trial.ab.

20. groups.ab.

21. or/13-20

22. (animals not (humans and animals)).sh.

23. 21 not 22

24. and/3,12,23

 

 

Appendix 2. EMBASE search strategy

1     exp rheumatoid arthritis/

2     ((rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or rheumat$ or reumat$ or revmarthrit$) adj3 (arthrit$ or artrit$ or diseas$ or condition$ or nodule$)).tw.

3     1 or 2

4     exp fatigue/

5     fatigue$.tw.

6     (tired$ or weary or weariness or exhaustion or exhausted).tw.

7     ((astenia or asthenic) and syndrome).tw.

8     ((lack or loss or lost) adj3 (energy or vigo?r)).tw.

9     (apath$ or lassitude or weak$ or letharg$).tw.

10     (feel$ adj3 (drained or sleep$ or sluggish)).tw.

11     vitality.tw.

12     or/4-11

13     3 and 12

14     random$.ti,ab.

15     factorial$.ti,ab.

16     (crossover$ or cross over$ or cross-over$).ti,ab.

17     placebo$.ti,ab.

18     (doubl$ adj blind$).ti,ab.

19     (singl$ adj blind$).ti,ab.

20     assign$.ti,ab.

21     allocat$.ti,ab.

22     volunteer$.ti,ab.

23     crossover procedure.sh.

24     double blind procedure.sh.

25     randomized controlled trial.sh.

26     single blind procedure.sh.

27     or/14-26

28     exp animal/ or nonhuman/ or exp animal experiment/

29     exp human/

30     28 and 29

31     28 not 30

32     27 not 31

33     13 and 32

 

Appendix 3. CENTRAL search strategy

#1      MeSH descriptor Arthritis, Rheumatoid explode all trees

#2      ((rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or       rheumat* or reumat* or revmarthrit*) near/3 (arthrit* or artrit* or diseas* or         condition* or nodule*)):ti,ab

#3      (#1 OR #2)

#4      MeSH descriptor Fatigue explode all trees

#5      fatigue*:ti,ab

#6      (tired* or weary or weariness or exhaustion or exhausted):ti,ab

#7      ((astenia or asthenic) and syndrome):ti,ab

#8      ((lack or loss or lost) near/3 (energy or vigor)):ti,ab

#9      (apath* or lassitude or weak* or letharg*):ti,ab

#10    (feel* near/3 (drained or sleep* or sluggish)):ti,ab

#11    vitality:ti,ab

#12    (#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11)

#13    (#3 AND #12)

 

Appendix 4. CINAHL search strategy

S75        S61 and S74

S74        S62 or S63 or S64 or S65 or S66 or S67 or S68 or S69 or S70 or S71 or S72 or S73

S73        TI Allocat* random* or AB Allocat* random*

S72        (MH "Quantitative Studies")

S71        (MH "Placebos")

S70        TI Placebo* or AB Placebo*

S69        TI Random* allocat* or AB Random* allocat*

S68        (MH "Random Assignment")

S67        TI Randomi?ed control* trial* or AB Randomi?ed control* trial*

S66        AB singl* blind* or AB singl* mask* or AB doub* blind* or AB doubl* mask* or AB trebl* blind* or AB trebl* mask* or AB tripl* blind* or AB tripl* mask*

S65        TI singl* blind* or TI singl* mask* or TI doub* blind* or TI doubl* mask* or TI trebl* blind* or TI trebl* mask* or TI tripl* blind* or TI tripl* mask*

S64        TI clinical* trial* or AB clinical* trial*

S63        PT clinical trial

S62        (MH "Clinical Trials+")

S61        S42 and S60

S60        S43 or S44 or S45 or S46 or S47 or S48 or S49 or S50 or S51 or S52 or S53 or S54 or S55 or S56 or S57 or S58 or S59

S59        ti vitality or ab vitality

S58        ab feel* N3 drain* or ab feel* N3 sleep* or ab feel* N3 sluggish

S57        ti feel* N3 drain* or ti feel* N3 sleep* or ti feel* N3 sluggish

S56        ab apath* or ab lassitude or ab weak* or ab letharg*

S55        ti apath* or ti lassitude or ti weak* or ti letharg*

S54        ab lack N3 vigour or abloss N3 vigour or ab lost N3 vigour

S53        ti lack N3 vigour or ti loss N3 vigour or ti lost N3 vigour

S52        ab lack N3 vigor or ab loss N3 vigor or ab lost N3 vigor

S51        ti lack N3 vigor or ti loss N3 vigor or ti lost N3 vigor

S50        ti lack N3 vigor or ti loss N3 vigor or ab lost N3 vigor

S49        ti lack N3 energy or ti loss N3 energy or ti lost N3 energy

S48        ab astenia syndrome or ab asthenic syndrome

S47        ti astenia syndrome or ti asthenic syndrome

S46        ab tired* or weary or weariness or exhaustion or exhausted

S45        ti tired* or weary or weariness or exhaustion or exhausted

S44        ti fatigue* or ab fatigue*

S43        (MH "Fatigue+")

S42        S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33 or S34 or S35 or S36 or S37 or S38 or S39 or S40 or S41

S41        TI reumat* N3 nodule* or AB reumat* N3 nodule*

S40        TI reumat* N3 condition* or AB reumat* N3 condition*

S39        TI reumat* N3 diseas* or AB reumat* N3 diseas*

S38        TI reumat* N3 artrit* or AB reumat* N3 artrit*

S37        TI reumat* N3 arthrit* or AB reumat* N3 arthrit*

S36        TI revmarthrit* N3 nodule* or AB revmarthrit* N3 nodule*

S35        TI revmarthrit* N3 condition* or AB revmarthrit* N3 condition*

S34        TI revmarthrit* N3 diseas* or AB revmarthrit* N3 diseas*

S33        TI revmarthrit* N3 artrit* or AB revmarthrit* N3 artrit*

S32        TI revmarthrit* N3 arthrit* or AB revmarthrit* N3 arthrit*

S31        TI rheumat* N3 nodule* or AB rheumat* N3 nodule*

S30        TI rheumat* N3 condition* or AB rheumat* N3 condition*

S29        TI rheumat* N3 diseas* or AB rheumat* N3 diseas*

S28        TI rheumat* N3 artrit* or AB rheumat* N3 artrit*

S27        TI rheumat* N3 arthrit* or AB rheumat* N3 arthrit*

S26        TI revmatic N3 nodule* or AB revmatic N3 nodule*

S25        TI revmatic N3 condition* or AB revmatic N3 condition*

S24        TI revmatic N3 diseas* or AB revmatic N3 diseas*

S23        TI revmaticN3 artrit* or AB revmatic N3 artrit*

S22        TI revmatic N3 arthrit* or AB revmatic N3 arthrit*

S21        TI rheumatic N3 nodule* or AB rheumatic N3 nodule*

S20        TI rheumatic N3 condition* or AB rheumatic N3 condition*

S19        TI rheumatic N3 diseas* or AB rheumatic N3 diseas*

S18        TI rheumatic N3 artrit* or AB rheumatic N3 artrit*

S17        TI rheumatic N3 arthrit* or AB rheumatic N3 arthrit*

S16        TI revmatoid N3 nodule* or AB revmatoid N3 nodule*

S15        TI revmatoid N3 condition* or AB revmatoid N3 condition*

S14        TI revmatoid N3 diseas* or AB revmatoid N3 diseas*

S13        TI revmatoid N3 artrit* or AB revmatoid N3 artrit*

S12        TI revmatoid N3 arthrit* or AB revmatoid N3 arthrit*

S11        TI reumatoid N3 nodule* or AB reumatoid N3 nodule*

S10        TI reumatoid N3 condition* or AB reumatoid N3 condition*

S9          TI reumatoid N3 diseas* or AB reumatoid N3 diseas*

S8          TI reumatoid N3 artrit* or AB reumatoid N3 artrit*

S7          TI reumatoid N3 arthrit* or AB reumatoid N3 arthrit*

S6          TI rheumatoid N3 nodule* or AB rheumatoid N3 nodule*

S5          TI rheumatoid N3 condition* or AB rheumatoid N3 condition*

S4          TI rheumatoid N3 diseas* or AB rheumatoid N3 diseas*

S3          TI rheumatoid N3 artrit* or AB rheumatoid N3 artrit* *

S2          TI rheumatoid N3 arthrit* or AB rheumatoid N3 arthrit*

S1          (MH "Arthritis, Rheumatoid+")

 

Appendix 5. PsycINFO search strategy

1. rheumatoid arthritis/

2. ((rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or rheumat$ or reumat$ or revmarthrit$) adj3 (arthrit$ or artrit$ or diseas$ or condition$ or nodule$)).tw.

3. 1 or 2

4. Fatigue/

5. fatigue$.tw.

6. (tired$ or weary or weariness or exhaustion or exhausted).tw.

7. ((astenia or asthenic) and syndrome).tw.

8. ((lack or loss or lost) adj3 (energy or vigo?r)).tw.

9. (apath$ or lassitude or weak$ or letharg$).tw.

10. (feel$ adj3 (drained or sleep$ or sluggish)).tw.

11. vitality.tw.

12. or/4-11

 

Appendix 6. AMED search strategy

1. exp arthritis, rheumatoid/

2. ((rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or rheumat$ or reumat$ or revmarthrit$) adj3 (arthrit$ or artrit$ or diseas$ or condition$ or nodule$)).tw.

3. 1 or 2

4. exp Fatigue/

5. fatigue$.tw.

6. (tired$ or weary or weariness or exhaustion or exhausted).tw.

7. ((astenia or asthenic) and syndrome).tw.

8. ((lack or loss or lost) adj3 (energy or vigo?r)).tw.

9. (apath$ or lassitude or weak$ or letharg$).tw.

10. (feel$ adj3 (drained or sleep$ or sluggish)).tw.

11. vitality.tw.

12. or/4-11

13. 3 and 12

 

Appendix 7. Web of Science search strategy

Topic=((rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or rheumat* or reumat* or revmarthrit*) and (arthrit* or artrit* or diseas* or condition* or nodule*)) AND Topic=(fatigue* or tired* or weary or weariness or exhaustion or exhausted or astenia syndrome or asthenic syndrome or apath* or

lassitude or weak* or

(lack or loss or lost) and (letharg* or energy or vigoor* or vigour*) or

Feel* and (drained or sleep* or sluggish)

(trial* or random* or placebo* or control* or double or treble or triple or blind* or mask* or allocat* or prospective* or volunteer*or comparative or evaluation or follow-up or followup)

 

Appendix 8. Dissertation Abstracts search strategy

(rheumatoid or reumatoid or revmatoid or rheumatic or reumatic or revmatic or rheumat* or reumat* or revmarthrit*) in citation and abstract

AND (fatigue* or tired* or weary or weariness or exhaustion or exhausted or astenia syndrome or asthenic syndrome or apath* or lassitude or weak* or letharg* or energy or vigoor* or vigour* or drained or sleep* or sluggish) in citation and abstract

 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Protocol first published: Issue 1, 2010
Review first published: Issue 8, 2013


DateEventDescription

5 March 2012AmendedCMSG ID: C195-R



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

All authors contributed to the initial draft protocol as well as to the review process and commented on at least one complete draft of the full review. Fiona Cramp, Celia Almeida and Sarah Hewlett worked in collaboration on refining all parts of the protocol, incorporating comments from members of the wider review group. Fiona Cramp and Sarah Hewlett led on the development of the final review with input from all authors.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

The authors do not have any conflicts of interest.

At the time of protocol development Sarah Hewlett was in receipt of a small unrestricted educational grant from GlaxoSmithKline to partially fund a PhD studentship on fatigue measurement in RA. She was also undertaking an RCT of cognitive behavioural therapy for the self-management of RA fatigue, funded by the Arthritis Research Campaign. During the full review process Sarah Hewlett also received a small consultancy fee from UCB Pharmaceuticals to advise on the translatation of the Bristol RA Fatigue Scales. These associations reflect our large programme of research in fatigue into RA but do not constitute a conflict of interests.

Professor Ernest Choy has received research grants, and served as member of advisory boards and speaker bureaus of Abbott Laboratories, Allergan, AstraZeneca, Boehringer Ingelheim, Chelsea Therapeutics, Chugai Pharma, Daiichi Sankyo, Eli Lilly, Ferring Pharmacuetical, GSK, ISIS, Jazz Pharmaceuticals, MedImmune, Merrimack Pharmaceutical, MSD, Novartis, Pfizer, Pierre Fabre Medicament, Roche, Schering Plough, Synovate, and UCB. These activities do not constitute a conflict of interest.

Professor Robin Christensen has received grant support and/or provided expert advice and/or presentations for Abbott/AbbVie, Axellus, Bayer HealthCare Pharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Cambridge Weight Plan, Ipsen, Laboratoires Expanscience, MSD, Mundipharma, Norpharma, Pfizer, Roche, and Wyeth. He reports being involved in health-care initiatives and research that could benefit from wide uptake of comparative effectiveness research (including Cochrane Collaboration, OMERACT, and the GRADE Working Group) but these do not constitute a conflict of interest.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • Arthritis Research UK, UK.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
Bilberg 2005 {published data only}
  • Bilberg A, Ahlmen M, Mannerkorpi K. Moderately intensive exercise in a temperate pool for patients with rheumatoid arthritis: a randomized controlled study. Rheumatology (Oxford) 2005;44(4):502-8.
Burgos 2009 {published data only}
  • Burgos RA, Hancke JL, Bertoglio JC, Aguirre V, Arriagada S, Calvo M, et al. Efficacy of an Andrographis paniculata composition for the relief of rheumatoid arthritis symptoms: A prospective randomized placebo-controlled trial. Clinical Rheumatology 2009;28(8):931-46.
Danoff-Burg 2006 - I {published data only}
  • Danoff-Burg S, Agee JD, Romanoff NR, Kremer JM, Strosberg JM. Benefit finding and expressive writing in adults with lupus or rheumatoid arthritis. Psychology & Health 2006;21(5):651-65.
Danoff-Burg 2006 - II {published data only}
  • Danoff-Burg S, Agee JD, Romanoff NR, Kremer JM, Strosberg JM. Benefit finding and expressive writing in adults with lupus or rheumatoid arthritis. Psychology & Health 2006;21(5):651-65.
Das Gupta 2009 {published data only}
  • Das Gupta AB, Hossain AK, Islam MH, Dey SR, Khan AL. Role of omega-3 fatty acid supplementation with indomethacin in suppression of disease activity in rheumatoid arthritis. Bangladesh Medical Research Council Bulletin 2009;35(2):63-8.
Evans 2012 {published and unpublished data}
  • Evans S, Lung K, Tsao J, Zeltzer L. Iyengar yoga for young adults with rheumatoid arthritis. Journal of Pain 2012;13 Suppl 4:s90.
Evers 2002 {published data only}
  • Evers AW, Kraaimaat FW, van Riel PL, de Jong AJ. Tailored cognitive-behavioral therapy in early rheumatoid arthritis for patients at risk: a randomized controlled trial. Pain 2002;100(1-2):141-53.
Furst 1987 {published data only}
  • Furst GP, Gerber LH, Smith CC, Fisher S, Shulman B. A program for improving energy conservation behaviors in adults with rheumatoid arthritis. American Journal of Occupational Therapy 1987;41(2):102-11.
Giraudet-Le-Quintrec 2007 {published data only}
  • Giraudet-Le Quintrec JS, Mayoux-Benhamou A, Ravaud P, Champion K, Dernis E, Zerkak D, et al. Effect of a collective educational program for patients with rheumatoid arthritis: a prospective 12-month randomized controlled trial. Journal of Rheumatology 2007;34(8):1684-91.
  • Mayoux-Benhamou A, Giraudet-Le Quintrec JS, Ravaud P, Champion K, Dernis E, Zerkak D, et al. Influence of patient education on exercise compliance in rheumatoid arthritis: a prospective 12-month randomized controlled trial. Journal of Rheumatology 2008;35(2):216-23.
Hakkinen 2003 {published data only}
Hakkinen 2003-II {published data only}
Hammond 2008 {published data only}
  • Hammond A, Bryan J, Hardy A. Effects of a modular behavioural arthritis education programme: a pragmatic parallel-group randomized controlled trial. Rheumatology (Oxford) 2008;47(11):1712-8.
Harkcom 1985 {published data only}
Helliwell 1999 {published data only}
  • Helliwell PS, O'Hara M, Holdsworth J, Hesselden A, King T, Evans P. A 12-month randomized controlled trial of patient education on radiographic changes and quality of life in early rheumatoid arthritis. Rheumatology 1999;38:303-8.
Hewlett 2011 {published data only}
  • Hewlett S, Ambler N, Almeida C, Cliss A, Hammond A, Kitchen K, et al. Self-management of fatigue in rheumatoid arthritis: a randomised controlled trial of a group cognitive-behavioural therapy. Annals of the Rheumatic Diseases 2011;70:1060-7.
Huffstutter 2007 {published data only}
  • Huffstutter J, Craig WD, Schimizzi G, Harshbarger J, Lisse J, Kasle S, et al. A multicenter, randomized, open study to evaluate the impact of an electronic data capture system on the care of patients with rheumatoid arthritis. Current Medical Research and Opinion 2007;23(8):1967-79.
Laforest 2008 {published data only}
  • Laforest S, Nour K, Gignac M, Gauvin L, Parisien M, Poirier M C. Short-term effects of a self-management intervention on health status of housebound older adults with arthritis. Journal of Applied Gerontology 2008;27(5):539-67.
Lorig 2005 {published data only}
Lorig 2008 {published data only}
Lumley 2011-I {published and unpublished data}
  • Lumley MA, Keefe FJ, Slatcher R, Mosley-Williams A,   Rice J, Mayo A, et al. The raised trial: Effects of coping skills training and written emotional disclosure on daily diary outcomes for patients with rheumatoid arthritis. Psychosomatic Medicine 2011;73(4):164.
Lumley 2011-II {published data only}
  • Lumley MA, Keefe FJ, Slatcher R, Mosley-Williams A,   Rice J, Mayo A, et al. The raised trial: Effects of coping skills training and written emotional disclosure on daily diary outcomes for patients with rheumatoid arthritis. Psychosomatic Medicine 2011;73(4):164.
Neuberger 2007 - I {published data only}
Neuberger 2007 - II {published data only}
Otter 2010 {published and unpublished data}
  • Otter S, Church A, Murray A, Lucas J, Creasey N, Woodhouse J, et al. The effects of reflexology in reducing the symptoms of fatigue in people with rheumatoid arthritis: a preliminary study. The Journal of Alternative and Complementary Medicine 2010;16(12):1251-2.
Riemsma 2003 - I {published data only}
Riemsma 2003 - II {published data only}
Skoldstam 2003 {published data only}
Wang 2008 {published data only}
  • Wang C. Tai Chi improves pain and functional status in adults with rheumatoid arthritis: results of a pilot single-blinded randomized controlled trial. Medicine and Sport Science 2008;52:218-29.
Zangi 2012 {published and unpublished data}
  • Zangi HA, Mowinckel P, Finset A, Eriksson LR, Høystad TØ, Lunde AK, Hagen KB. A mindfulness-based group intervention to reduce psychological distress and fatigue in patients with inflammatory rheumatic joint diseases: a randomised controlled trial. Annals of the Rheumatic Diseases 2012;71:911-7.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
Barlow 1998 {published data only}
  • Barlow JH, Turner AP, Wright CC. Long-term outcomes of an arthritis self-management programme. British Journal of Rheumatology 1998;37(12):1315-9.
Barlow 2000 {published data only}
Barlow 2009 {published data only}
Behandling og traening {published data only}
  • Behandling og traening. Danske Fysioter 2000; Vol. 12:11-3.
Bhat 2008 {published data only}
  • Bhat A. Literacy in arthritis. North Carolina, USA: The University of North Carolina at Chapel Hill, 2008:146.
Bhat 2010 {published data only}
  • Bhat AA, DeWalt DA, Zimmer CR, Fried BJ, Callahan LF. The role of helplessness, outcome expectation for exercise and literacy in predicting disability and symptoms in older adults with arthritis. Patient Education and Counseling 2010;81:73-8.
Callahan 2008 {published data only}
Daltroy 1995 {published data only}
  • Daltroy LH, Robb-Nicholson C, Iversen MD, Wright EA, Liang MH. Effectiveness of minimally supervised home aerobic training in patients with systemic rheumatic disease. British Journal of Rheumatology 1995;34(11):1064-9.
de Buck 2005 {published data only}
  • de Buck PD, le Cessie S, van den Hout WB, Peeters AJ, Ronday HK, Westedt ML, et al. Randomized comparison of a multidisciplinary job-retention vocational rehabilitation program with usual outpatient care in patients with chronic arthritis at risk for job loss. Arthritis and Rheumatism 2005;53(5):682-90.
Evers 2005 {published data only}
  • Evers AWM. Cognitive-behavioral therapy in rheumatoid arthritis [Dutch]. Nederlands Tijdschrift Voor Fysiotherapie 2005;115(5):143-6.
Furst 2000 {published data only}
  • Furst D, Felson D, Thoren G, Gendreau RM. Immunoadsorption for the treatment of rheumatoid arthritis: final results of a randomized trial. Prosorba Trial Investigators. Therapeutic Apheresis 2000;4(5):363-73.
Goldbach-Mansky 2009 {published data only}
  • Goldbach-Mansky R, Wilson M, Fleischmann R, Olsen N, Silverfield J, Kempf P, et al. Comparison of Tripterygium wilfordii Hook F versus sulfasalazine in the treatment of rheumatoid arthritis: A randomized trial. Annals of Internal Medicine 2009;151(4):229-40.
Hagfors 2003 {published data only}
  • Hagfors LM. A Mediterranean dietary intervention study of patients with rheumatoid arthritis [PhD Thesis]. Sweden: Umea Universitet (Sweden), 2003:184.
Hagfors 2005 {published data only}
  • Hagfors L, Nilsson I, Skoldstam L, Johansson G, Hagfors L, Nilsson I, et al. Fat intake and composition of fatty acids in serum phospholipids in a randomized, controlled, Mediterranean dietary intervention study on patients with rheumatoid arthritis. Nutrition and Metabolism 2005;2:26.
He 2008 {published data only}
  • He Y, Lu A, Lu C, Zha Y, Yan X, Song Y, et al. Symptom combinations assessed in traditional Chinese medicine and its predictive role in ACR20 efficacy response in rheumatoid arthritis. American Journal of Chinese Medicine 2008;36(4):675-83.
Heiberg 2007 {published data only}
Jiang 2012 {published data only}
  • Jiang M, Zha Q, He Y, Lu A. Risk factors of gastrointestinal and hepatic adverse drug reactions in the treatment of rheumatoid arthritis with biomedical combination therapy and Chinese medicine. Journal of Ethnopharmacology 2012;141:615-21.
Kremer 1987 {published data only}
  • Kremer JM, Jubiz W, Michalek A, Rynes RI, Bartholomew LE, Bigaquette J, et al. Fish-oil fatty acid supplementation in active rheumatoid arthritis. Annals of Internal Medicine 1987;106(4):497-503.
Lee 2006 {published data only}
  • Lee KY, Jeong OY, Lee K-Y, Jeong O-Y. The effect of Tai Chi movement in patients with rheumatoid arthritis. Taehan Kanho Hakhoe Chi 2006;36(2):278-85.
MacDonald 1994 {published data only}
Minnock 2008 {published data only}
  • Minnock P, Bresnihan B. Fatigue is related to poor pain outcomes in women with established rheumatoid arthritis. Clinical and Experimental Rheumatology 2008;26(4):707-8.
Mur 2002 {published data only}
  • Mur E, Hartig F, Eibl G, Schirmer M. Randomized double blind trial of an extract from the pentacyclic alkaloid-chemotype of uncaria tomentosa for the treatment of rheumatoid arthritis. Journal of Rheumatology 2002;29(4):678-81.
Neuberger 1997 {published data only}
  • Neuberger GB, Press AN, Lindsley HB, Hinton R, Cagle PE, Carlson K, et al. Effects of exercise on fatigue, aerobic fitness, and disease activity measures in persons with rheumatoid arthritis. Research in Nursing & Health 1997;20(3):195-204.
Nordemar 1981 {published data only}
  • Nordemar R. Physical training in rheumatoid arthritis: A controlled long-term study. II. Functional capacity and general attitudes. Scandinavian Journal of Rheumatology 1981;10(1):25-30.
Noreau 1995 {published data only}
  • Noreau L, Martineau H, Roy L, Belzile M. Effects of a modified dance-based exercise on cardiorespiratory fitness, psychological state and health status of persons with rheumatoid arthritis. American Journal of Physical Medicine and Rehabilitation 1995;74(1):19-27.
O'Leary 1986 {published data only}
  • O'Leary AM. Psychological factors in rheumatoid arthritis pain and immune function: a self-efficacy approach [PhD Thesis]. United States - California: Stanford University, 1986:209.
Pan 2009 {published data only}
Poulsen 1991 {published data only}
  • Poulsen A. Psychodynamic, time-limited group therapy in rheumatic disease: A controlled study with special reference to alexithymia. Psychotherapy and Psychosomatics 1991;56(1-2):12-23.
Rall 1996 {published data only}
  • Rall LC, Meydani SN, Kehayias JJ, Dawson-Hughes B, Roubenoff R. The effect of progressive resistance training in rheumatoid arthritis. Increased strength without changes in energy balance or body composition. Arthritis and Rheumatism 1996;39(3):415-26.
Rauma 1993 {published data only}
  • Rauma AL, Nenonen M, Helve T, Hanninen O. Effect of a strict vegan diet on energy and nutrient intakes by Finnish rheumatoid patients. European Journal of Clinical Nutrition 1993;47(10):747-9.
Solomon 2002 {published data only}
  • Solomon DH, Warsi A, Brown-Stevenson T, Farrell M, Gauthier S, Mikels D, et al. Does self-management education benefit all populations with arthritis? A randomized controlled trial in a primary care physician network. Journal of Rheumatology 2002;29(2):362-8.
Song 2007 {published data only}
  • Song YW, Lee EY, Koh EM, Cha HS, Yoo B, Lee CK, et al. Assessment of comparative pain relief and tolerability of SKI306X compared with celecoxib in patients with rheumatoid arthritis: A 6-week, multicenter, randomized, double-blind, double-dummy, phase III, noninferiority clinical trial. Clinical Therapeutics 2007;29(5):862-73.
Stenstrom 1993 {published data only}
  • Stenstrom CH. Dynamic therapeutic exercise in rheumatoid arthritis: Qualitative and quantitative aspects [PhD Thesis]. Sweden: Karolinska Institutet (Sweden), 1993:128.
Stenstrom 1994 {published data only}
  • Stenstrom CH. Home exercise in rheumatoid arthritis functional class II: goal setting versus pain attention. Journal of Rheumatology 1994;21(4):627-34.
Stenstrom 1996 {published data only}
  • Stenstrom CH, Arge B, Sundbom A. Dynamic training versus relaxation training as home exercise for patients with inflammatory rheumatic diseases. A randomized controlled study. Scandinavian Journal of Rheumatology 1996;25(1):28-33.
Taibi 2009 {published data only}
Toirov 2010 {published data only}
  • Toirov ES, Imamov AKh. Peculiarities of therapy of neurotic disorders in patients with rheumatoid arthritis. Klinicheskaia Meditsina 2010;88(1):49-53.

References to studies awaiting assessment

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
Berbert 2005 {published data only}
Wiesenauer 1991 {published data only}
  • Wiesenauer M, Gaus W. A randomized double blind trial on the efficiency of a homeopathic drug for rheumatoid arthritis. Aktuelle Rheumatologie 1991;16(1):1-9.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. Additional references
Arnett 1988
Brosseau 2005
Cameron 2011
Casimiro 2002
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Casimiro 2005
Chinn 2000
Cohen 1998
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Hagen 2009
Han 2004
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Hewlett 2011b
Hewlett 2011c
  • Hewlett S, Ambler N, Almeida C, Cliss A, Hammond A, Kitchen K, et al. Self-management of fatigue in rheumatoid arthritis: a randomised controlled trial of group cognitive behavioural therapy. Annals of the Rheumatic Diseases 2011;70:1060-7.
Higgins 2003
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Hurkmans 2009
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Pelland 2002
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Pollard 2006
Riemsma 2003
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Schünemann 2008
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Silva 2010
Treharne 2009
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Tuntland 2009
Verhagen 2004
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Welch 2002
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