Non-pharmacological interventions for fatigue in rheumatoid arthritis

  • Review
  • Intervention

Authors


Abstract

Background

Fatigue is a common and potentially distressing symptom for people with rheumatoid arthritis with no accepted evidence based management guidelines. Non-pharmacological interventions, such as physical activity and psychosocial interventions, have been shown to help people with a range of other long-term conditions to manage subjective fatigue.

Objectives

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.

Search methods

The following electronic databases were searched up to October 2012, Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; AMED; CINAHL; PsycINFO; Social Science Citation Index; Web of Science; Dissertation Abstracts International; Current Controlled Trials Register; The National Research Register Archive; The UKCRN Portfolio Database. In addition, reference lists of articles identified for inclusion were checked for additional studies and key authors were contacted.

Selection criteria

Randomised controlled trials were included if they evaluated a non-pharmacological intervention in people with rheumatoid arthritis with self-reported fatigue as an outcome measure.

Data collection and analysis

Two review authors selected relevant trials, assessed risk of bias and extracted data. Where appropriate, data were pooled using meta-analysis with a random-effects model.

Main results

Twenty-four studies met the inclusion criteria, with a total of 2882 participants with rheumatoid arthritis. Included studies investigated physical activity interventions (n = 6 studies; 388 participants), psychosocial interventions (n = 13 studies; 1579 participants), herbal medicine (n = 1 study; 58 participants), omega-3 fatty acid supplementation (n = 1 study; 81 participants), Mediterranean diet (n = 1 study; 51 participants), reflexology (n = 1 study; 11 participants) and the provision of Health Tracker information (n = 1 study; 714 participants). Physical activity was statistically significantly more effective than the control at the end of the intervention period (standardized mean difference (SMD) -0.36, 95% confidence interval (CI) -0.62 to -0.10; back translated to mean difference of 14.4 points lower, 95% CI -4.0 to -24.8 on a 100 point scale where a lower score means less fatigue; number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 4 to 26) demonstrating a small beneficial effect upon fatigue. Psychosocial intervention was statistically significantly more effective than the control at the end of the intervention period (SMD -0.24, 95% CI -0.40 to -0.07; back translated to mean difference of 9.6 points lower, 95% CI -2.8 to -16.0 on a 100 point scale, lower score means less fatigue; NNTB 10, 95% CI 6 to 33) demonstrating a small beneficial effect upon fatigue. For the remaining interventions meta-analysis was not possible and there was either no statistically significant difference between trial arms or findings were not reported. Only three studies reported any adverse events and none of these were serious, however, it is possible that the low incidence was in part due to poor reporting. The quality of the evidence ranged from moderate quality for physical activity interventions and Mediterranean diet to low quality for psychosocial interventions and all other interventions.

Authors' conclusions

This review provides some evidence that physical activity and psychosocial interventions provide benefit in relation to self-reported fatigue in adults with rheumatoid arthritis. There is currently insufficient evidence of the effectiveness of other non-pharmacological interventions.

Résumé scientifique

Interventions non pharmacologiques contre la fatigue dans la polyarthrite rhumatoïde

Contexte

La fatigue est un symptôme courant et potentiellement pénible pour les personnes souffrant de polyarthrite rhumatoïde sans que l'on dispose de preuves acceptées fondées sur les recommandations de prise en charge. Il s'avère que les interventions non pharmacologiques, comme une activité physique et les interventions psychosociales, aident les personnes présentant tout un éventail d'autres pathologies à long terme à prendre en charge la fatigue subjective.

Objectifs

Évaluer les bénéfices et les risques des interventions non pharmacologiques pour la prise en charge de la fatigue chez les patients souffrant de polyarthrite rhumatoïde. Cela incluait toute intervention qui n'était pas classée dans les traitements pharmacologiques conformément à la Directive 2001/83/CEE de l'Union européenne (UE).

Stratégie de recherche documentaire

Nous avons effectué des recherches dans les bases de données électroniques suivantes jusqu'à octobre 2012, le registre Cochrane des essais contrôlés (CENTRAL) ; MEDLINE ; EMBASE ; AMED ; CINAHL ; PsycINFO ; Social Science Citation Index ; Web of Science ; Dissertation Abstracts International ; le registre des essais contrôlés en cours ; le National Research Register Archive ; la base de données UKCRN Portfolio Database. En outre, les références bibliographiques des articles identifiés pour l'inclusion ont été vérifiées pour trouver des études supplémentaires et des auteurs majeurs ont été contactés.

Critères de sélection

Les essais contrôlés randomisés ont été inclus s'ils avaient évalué une intervention non pharmacologique chez les personnes souffrant de polyarthrite rhumatoïde avec la fatigue rapportée par le patient comme critère de jugement mesuré.

Recueil et analyse des données

Deux auteurs ont sélectionné les essais pertinents, évalué le risque de biais et extrait les données. Lorsque cela était approprié, les données ont été regroupées dans une méta-analyse en utilisant un modèle à effets fixes.

Résultats principaux

Vingt-quatre études répondaient aux critères d’inclusion et totalisaient 2 882 participants souffrant de polyarthrite rhumatoïde. Les études incluses ont examiné des interventions axées sur l'activité physique (n = 6 études ; 388 participants), des interventions psychosociales (n = 13 études ; 1 579 participants), des plantes médicinales (n = 1 étude ; 58 participants), la supplémentation en acides gras riches en oméga-3 (n = 1 étude ; 81 participants), le régime méditerranéen (n = 1 étude ; 51 participants), la réflexologie (n = 1 étude ; 11 participants) et la mise à disposition des informations de veille sanitaire (n = 1 étude ; 714 participants). L'activité physique a été au plan statistique nettement plus efficace que l'intervention témoin à la fin de la période d'intervention (différence moyenne standardisée (DMS) -0,36, intervalle de confiance (IC) à 95 % -0,62 à -0,10 ; convertie en différence moyenne de 14,4 points plus basse, IC à 95 % -4,0 à -24,8 sur une échelle en 100 points où un score inférieur indique une fatigue moindre ; nombre de sujets à traiter pour tirer un bénéfice supplémentaire (NNTB) de 7, IC à 95 % 4 à 26) révélant un petit effet bénéfique sur la fatigue. Les interventions psychosociales ont été au plan statistique nettement plus efficace que l'intervention témoin à la fin de la période d'intervention (DMS -0,24, IC à 95 % -0,40 à -0,07 ; convertie en différence moyenne de 9,6 points plus basse, IC à 95 % -2,8 à -16,0 sur une échelle en 100 points où un score inférieur indique une fatigue moindre ; NNTB 10, IC à 95 % 6 à 33) révélant un petit effet bénéfique sur la fatigue. Pour le reste des interventions, il n'a pas été possible de réaliser une méta-analyse et soit il n'y avait aucune différence statistiquement significative entre les bras des essais soit les résultats n'avaient pas été rapportés. Trois études uniquement ont rapporté des événements indésirables et aucun d'entre eux n'a été grave, toutefois, il est possible que la faible incidence ait été due en partie à la mauvaise méthode de notification des résultats. La qualité des preuves allait d'une qualité modérée pour les interventions axées sur l'activité physique et le régime méditerranéen, à une faible qualité pour les interventions psychosociales et toutes les autres interventions.

Conclusions des auteurs

Cette revue apporte quelques preuves que l'activité physique et les interventions psychosociales entraînent un bénéfice en ce qui concerne la fatigue rapportée par le patient chez l'adulte souffrant de polyarthrite rhumatoïde. À l'heure actuelle, les preuves de l'efficacité des autres interventions non pharmacologiques sont insuffisantes.

アブストラクト

関節リウマチにおける疲労に対する非薬理学的介入

背景

疲労は関節リウマチ患者によくみられ、苦痛を伴う症状となりうるが、治療指針に基づく認められたエビデンスがない。身体活動的および心理社会的介入などの非薬理学的介入は、さまざまな他の慢性疾患を有する人々の主観的疲労の管理に役立つことが示されている。

目的

関節リウマチ患者を対象として、疲労管理に対する非薬理学的介入の利益と有害性を検討すること。欧州連合(EU)Directive 2001/83/EECに従い、薬理学的介入に分類されないすべての介入が含まれた。

検索戦略

次に挙げる電子データベースを2012年10月まで検索した:Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; AMED; CINAHL; PsycINFO; Social Science Citation Index; Web of Science; Dissertation Abstracts Inter- national; Current Controlled Trials Register; The National Research Register Archive; The UKCRN Prtfolio Database。また、組み入れに同定した記事の引用先リストについては追加的な研究の有無を確認し、主著者に連絡をとった。

選択基準

自己報告による疲労を有する関節リウマチ患者への非薬理学的介入をアウトカム指標として評価したランダム化比較試験を組み入れた。

データ収集と分析

2名のレビュー著者が関連する研究を選択し、バイアスのリスクを評価し、データを抽出した。必要に応じて、メタアナリシスの変量効果モデルを用いてデータを併合した。

主な結果

24試験(関節リウマチ患者2882名)が組み入れ基準に合致した。選択した研究では、次の介入を対象とした:身体活動的介入(n = 6試験、 388名)、心理社会的介入(n = 13試験、1579名)、漢方薬(n =1試験、58名)、オメガ3脂肪酸サプリメント(n =1試験、81名)、地中海式ダイエット(n =1試験、51名)、リフレクソロジー(n =1試験、11名)、ヘルストラッカー情報の提供(n =1試験、714名)。介入期間終了時に、身体的活動は対照群と比べて統計学的に有意に効果が認められ(標準化平均差[SMD]-0.36、95%信頼区間[CI] -0.62 ~-0.10、逆変換した平均差-14.4ポイント、95% CI -4.0 ~-24.8[100点満点で低値ほど疲労が少ない]、さらに有効なアウトカムに必要な治療数[NNTB]7, 95% CI 4~26)、疲労に対してわずかに有益な効果を示した。介入期間終了時に、心理社会的介入は対照群と比べて統計学的に有意に効果が認められ(SMD-0.24、95%CI-0.40~-0.07、逆変換した平均差-9.6ポイント、 95%CI-2.8~-16.0[100点満点で低値ほど疲労が少ない]、さらに有効なアウトカムに必要な治療数[NNTB]10, 95% CI 6~33)、疲労に対してわずかに有益な効果を示した。これら以外の介入についてはメタアナリシスが実施できず、群間に統計学的有意差はなく、知見は報告されていない。3研究でのみ有害事象が報告され、いずれも重篤ではなかったが、有害事象の発生率が低いのは報告が不十分だったためである可能性がある。エビデンスの質は、身体的活動介入と地中海式ダイエットについては中程度、心理社会的介入およびその他のすべての介入については低かった。

著者の結論

本レビューでは、身体的活動および心理社会的介入は、関節リウマチ患者の自己報告による疲労について利益があるとのいくつかのエビデンスが示された。その他の非薬理学的介入の有効性については現在のところ十分なエビデンスはない。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.7.11]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Plain language summary

Non-pharmacological interventions for the management of patient-reported fatigue in rheumatoid arthritis

This summary of a Cochrane review presents what we know from research that has investigated the effects of non-pharmacological treatments for fatigue in people with rheumatoid arthritis. 

After searching for all relevant studies, 24 were identified for inclusion in the review with a total of 2882 people. The findings are summarised as follows.

- Physical activity has a small benefit for managing fatigue in people with rheumatoid arthritis.

- Psychosocial therapy has a small benefit for managing fatigue in people with rheumatoid arthritis.

- No other interventions showed a difference in managing fatigue in people with rheumatoid arthritis. This may have happened by chance.

The information available regarding side effects and complications of the interventions was not very informative although it is unlikely that any side effects would cause a serious problem.

What is rheumatoid arthritis and what are non-pharmacological interventions?

When you have rheumatoid arthritis, your immune system, which normally fights infection, attacks the lining of your joints. This makes your joints swollen, stiff and painful. The small joints of your hands and feet are usually affected first. There is no cure for rheumatoid arthritis at present, so the treatments aim to relieve pain and stiffness and improve your ability to move. Fatigue is also a problem for people with rheumatoid arthritis.

Non-pharmacological interventions include any treatment that is not a registered drug, such as physical activity and psychosocial interventions (talking therapies). A talking therapy could include meeting with a counsellor, alone or in a group. It might involve writing about your thoughts and feelings in a journal and talking about it, problem-solving, setting goals and getting feedback about self-management. It might also include sessions on pain management and relaxation; and coping with depression. There are other non-pharmacological treatments that have been tested for their effect upon fatigue in people with rheumatoid arthritis. These include different dietary supplements and studies on the effects of giving people access to information about their own disease status. These treatments if supported by the overall body of evidence would allow the patient to have some personal control of their fatigue.

What happens to people with rheumatoid arthritis who use non-pharmacological interventions?

- At the end of the intervention, people receiving a control had a mean score of 63 on a scale of 0 to 100 with a lower score meaning less fatigue.

- People who used physical activity rated their fatigue as 54 on a scale of 0 to 100 at the end of the intervention, that is 9 points lower than the people who received the control.

- People who participated in a psychosocial intervention rated their fatigue as 57 on a scale of 0 to 100 at the end of the intervention, that is 6 points lower than the people who received the control.

Résumé simplifié

Interventions non pharmacologiques pour la prise en charge de la fatigue signalée par les patients dans la polyarthrite rhumatoïde

Ce résumé d’une revue Cochrane présente les connaissances tirées des recherches portant sur les effets des traitements non pharmacologiques contre la fatigue des patients souffrant de polyarthrite rhumatoïde. 

À l'issue de la recherche de toutes les études pertinentes, 24 ont été identifiées pour l'inclusion dans la revue avec un effectif total de 2 882 patients. Les résultats sont résumés ainsi.

- L'activité physique offre un petit bénéfice pour la prise en charge de la fatigue chez les personnes souffrant de polyarthrite rhumatoïde.

- La thérapie psychosociale offre un petit bénéfice pour la prise en charge de la fatigue chez les personnes souffrant de polyarthrite rhumatoïde.

- Aucune autre intervention n'a révélé de différence dans la prise en charge de la fatigue chez les personnes souffrant de polyarthrite rhumatoïde. Cela tient peut-être au hasard.

Les informations disponibles concernant les effets secondaires et les complications des interventions n'étaient pas très instructives bien qu'il soit improbable qu'un effet secondaire puisse entraîner un problème grave.

Qu’est-ce que la Polyarthrite rhumatoïde et que sont les Interventions non pharmacologiques ?

Lorsque vous souffrez d’une Polyarthrite rhumatoïde, votre système immunitaire, qui combat normalement les infections, attaque la paroi de vos articulations. Cela fait gonfler vos articulations et les rend raides et douloureuses. Les petites articulations de vos mains et de vos pieds sont généralement les premières touchées. Il n’existe à l’heure actuelle aucun remède pour la polyarthrite rhumatoïde et les traitements visent donc à soulager la douleur et la raideur, ainsi qu’à améliorer votre capacité à vous déplacer. La fatigue est aussi un problème pour les patients souffrant de polyarthrite rhumatoïde.

Les interventions non pharmacologiques comprennent tout traitement qui n'est pas un médicament enregistré, comme une activité physique et des interventions psychosociales (thérapies fondées sur la parole). Une thérapie fondée sur la parole pourrait inclure un rendez-vous avec un conseiller, individuellement ou dans un groupe. Cela peut consister à noter vos pensées et vos sentiments dans un journal et en parler, à résoudre les problèmes, à vous fixer des objectifs et à recevoir un retour de commentaires sur l'auto-prise en charge. Cela peut aussi inclure des séances consacrées à la prise en charge de la douleur et à la relaxation ; et l'adaptation à la dépression. D'autres traitements non pharmacologiques ont été testés pour déterminer leur effet sur la fatigue chez les personnes souffrant de polyarthrite rhumatoïde. Ils comprennent différents suppléments diététiques et des études sur les effets de l'accès par les personnes aux informations sur leur propre statut de la maladie. Ces traitements, s'ils sont corroborés par l'ensemble des données disponibles, devraient permettre au patient d'exercer un certain contrôle personnel sur sa fatigue.

Qu'arrive-t-il aux personnes souffrant de polyarthrite rhumatoïde qui utilisent des interventions non pharmacologiques ?

- À la fin de l'intervention, les personnes recevant une intervention témoin avaient un score moyen de 63 sur une échelle de 0 à 100, un score inférieur indiquant une fatigue moindre.

- Les personnes qui ont utilisé une activité physique ont noté leur fatigue à 54 sur une échelle de 0 à 100 à la fin de l'intervention, soit une note plus basse de 9 points que les personnes qui ont reçu l'intervention témoin.

- Les personnes qui ont participé à une intervention psychosociale ont noté leur fatigue à 57 sur une échelle de 0 à 100 à la fin de l'intervention, soit une note plus basse de 6 points que les personnes qui ont reçu l'intervention témoin.

Notes de traduction

Traduit par: French Cochrane Centre 16th October, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

平易な要約

関節リウマチ患者の自己報告による疲労の管理に対する非薬理学的介入

コクランレビューの本要約では、関節リウマチ患者の自己報告による疲労の非薬理学的治療の有効性について対象とした研究による知見を示す。 

関連するすべての研究を検索後、合計2882名を対象とした24研究をレビュー対象として同定した。知見を以下に要約する。

-身体的活動は関節リウマチ患者の疲労管理にわずかに利益がある。

-心理社会的療法は関節リウマチ患者の疲労管理にわずかに利益がある。

-その他の介入では、関節リウマチ患者の疲労管理において差異はみられなかった。これは偶然の効果による可能性がある。

副作用および介入による合併症について利用可能な情報はあまり有 益ではなかったが、副作用が重大な問題を引き起こす可能性は低い。

関節リウマチ、非薬理学的治療と

関節リウマチになると、通常は感染と闘っている免疫系が関節の裏層 を攻撃する。そのため、関節が腫れ、硬直し、痛みが生じる。通常、 最初に症状がみられるのは手足の小関節である。現在のところ関節リ ウマチに対する治療法はないため、治療は痛みや硬直の緩和と運動能 力の改善を目的とする。疲労も関節リウマチ患者にとって問題である。

非薬理学的介入には、身体的活動介入および心理社会的介入(会話療法)などの薬剤として登録されていない治療法が含まれる。会話療法では1人またはグループでカウンセラーと面談する。会話療法では、考えや気持ちを日誌に書いたり、話したり、問題解決、目標設定、自己管理についてフィードバックを得る。また、疼痛管理、リラクセーション、抑うつへの対処に関するセッションも含まれる。関節リウマチ患者で疲労に対する有効性を検証されてきた非薬理学的治療は他にもある。さまざまな栄養補助食品および疾患状態に関する情報入手の機会の患者への提供の有効性に関する研究などがある。これらの治療が体系的なエビデンスで支持されれば、患者は疲労をある程度自分自身で管理できるようになるだろう。

非薬理学的治療を行なうと関節リウマチ患者はどうなるのか。

-介入終了時に対照群の患者では100ポイント中63ポイント(低値ほど疲労が少ない)であった。

-身体的活動介入を受けた患者では介入終了時に疲労が100満点中54ポイントで、対照群と比べて9ポイント低い。

-心理社会的介入を受けた患者の疲労は100ポイント中57ポイントで対照群と比べて6ポイント低い。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.7.11]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Summary of findings(Explanation)

Summary of findings for the main comparison. Non-pharmacological interventions for rheumatoid arthritis
  1. 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

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
Control Non-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)
⊕⊕⊕⊝
moderate 3

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)
⊕⊕⊝⊝
low 3,4

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)
⊕⊕⊝⊝
low 5

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)
⊕⊕⊝⊝
low 5

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)
⊕⊕⊝⊝
low 6

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)
⊕⊕⊕⊝
moderate 5

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)

⊕⊕⊝⊝
low 4

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.

Background

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

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

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

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies

Results of the search

See: Figure 1

Figure 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

Table 1. Interventions
Study IDIntervention categorySpecific intervention
Bilberg 2005Physical activitypool-based therapy
Evans 2012Physical activityYoga
Hakkinen 2003Physical activitystrength training
Harkcom 1985Physical activitystationary cycling
Neuberger 2007 - IPhysical activityaerobic exercise
Wang 2008Physical activityTai Chi
Danoff-Burg 2006 - IPsychosocialbenefit finding and expressive writing
Lumley 2011-IPsychosocialcognitive skills training & written emotional disclosure
Evers 2002Psychosocialcognitive behavioural therapy
Hewlett 2011Psychosocialcognitive behavioural therapy
Zangi 2012Psychosocialmindfulness based group intervention
Hammond 2008Psychosociallifestyle management
Furst 1987Psychosocialeducation incorporating energy conservation
Laforest 2008Psychosocialeducation incorporating self management
Lorig 2005Psychosocialeducation incorporating self management
Lorig 2008Psychosocialeducation incorporating self management
Riemsma 2003 - IPsychosocialgroup education
Helliwell 1999Psychosocialgroup education
Giraudet-Le-Quintrec 2007Psychosocialgroup education
Skoldstam 2003OtherMediterranean diet
Burgos 2009Otherherbal medicine
Das Gupta 2009Otheromega-3 fatty acid supplementation
Huffstutter 2007Otherelectronic data capture system
Otter 2010Otherreflexology

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.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 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).

Figure 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).

Figure 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

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

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

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

Data and analyses

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]
Analysis 1.1.

Comparison 1 Physical activity versus control, Outcome 1 Fatigue.

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]
Analysis 2.1.

Comparison 2 Psychosocial versus control, Outcome 1 Fatigue.

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]
Analysis 3.1.

Comparison 3 Mediterranean diet versus control, Outcome 1 Fatigue.

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]
Analysis 4.1.

Comparison 4 Andrographis paniculata versus control, Outcome 1 Fatigue.

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]
Analysis 5.1.

Comparison 5 Omega-3 fatty acid versus control, Outcome 1 Fatigue.

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]
Analysis 6.1.

Comparison 6 Data tracker versus control, Outcome 1 Fatigue.

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]
Analysis 7.1.

Comparison 7 Reflexology versus control, Outcome 1 Fatigue.

Appendices

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

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

DateEventDescription
5 March 2012AmendedCMSG ID: C195-R

Contributions of authors

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

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

Internal sources

  • No sources of support supplied

External sources

  • Arthritis Research UK, UK.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bilberg 2005

MethodsRCT: 2 arms
ParticipantsRA for 1-5 years, 3 months stable medication, functional class I, II or III, age 20-65
InterventionsExercise in temperate pool twice a week in groups of 8-9: moderate intensity, paced by music, 2 alternating physiotherapists 
Outcomes

Primary: aerobic capacity and SF-36 physical component

Relevant secondary: disability (HAQ)

Other: disease activity (DAS28), arthritis impact measurement scale (AIMS2), health related quality of life (SF-36), Upper and lower extremity muscle endurance, function, Quality of life, active forward and lateral rotation of shoulder, hand grip force

ExclusionsOther severe diseases or functional limitations with pool training
Fatigue outcomesSF36 Vitality, High=good
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskOptimal allocation with a computer program
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated for personnel or participants. A physiotherapist blinded to study arm membership conducted the examinations
Incomplete outcome data (attrition bias)
All outcomes
Low riskData analysis carried out by protocol
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasHigh riskSome missing data. Two control patients exercised in the pool group

Burgos 2009

MethodsRCT: 2 arms
Participants18-70 years, active RA (at least 1 swollen joint, ESR >20mm/h or CRP >20mg/dl), MTX partial responders
Interventions30 mg andrographolides tablet 3 times/day for 14 weeks
Outcomes

Primary outcomes: reduction of joint pain, stiffness and tiredness

Relevant secondary: disability (HAQ)

Other: immunological parameters, health-related quality of life (SF36), rheumatoid factor, ESR, CRP, complete blood counts, X-rays (chest, hands and feet), venous blood for safety evaluations

ExclusionsOther non-degenerative/other joint diseases that could interfere with RA evaluation (gout, chondrocalcinosis, psoriatic arthritis, infectious arthritis, reactive or spondylitic arthritis), women with child-bearing potential, pregnant or breast feeding and patients with severely limiting arthritis that rendered them subject to surgery or severely crippling or prostrated patients. Use of intra-articular steroids the month before enrolment, concomitant treatment with hydantoin, lithium, or anticoagulant drugs. History of peptic ulcer, or gastrointestinal bleeding in the preceding 6 months. History of hypersensitivity or adverse effects to NSAIDs. Renal failure, hepatic failure, severe heart failure, haematologic disease, history of alcohol or drug abuse, participation in other research in the preceding month, patients not willing to attend regular check ups.
Fatigue outcomesVAS tiredness, range 0-100mm, High = bad
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"random codes with a permuted randomisation scheme were generated by computer"
Allocation concealment (selection bias)Low risk"Two envelopes contained each individual's treatment assignment"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskPatients and personnel not aware of assignment, no details re outcome assessors
Incomplete outcome data (attrition bias)
All outcomes
Low riskITT
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasLow riskNo evidence of other bias identified

Danoff-Burg 2006 - I

MethodsRCT: 3 arms
ParticipantsRA/Systemic Lupus Erythematosus (SLE), able to write for 20 minutes in English
InterventionsExpressive writing: encouraged participants to express their "deepest thoughts and feelings" about their experience with RA/SLE

Benefit finding: focus on "any positive thoughts and feelings" regarding their illness experience of RA/SLE

ALL arms had 3 week intervention, with 4 separate writing sessions within the 3-week period. Participants wrote alone in a private room in the laboratory for 20 minutes in accordance with their assigned instructions.
Outcomes

Primary: not stated

Relevant outcomes: Disability (HAQ), depression (CES-D), pain (VAS), anxiety (STAI)

Other: Profile of Mood States (POMS)

ExclusionsNone stated
Fatigue outcomesa) POMS Vigor 0-32, high=good
b) 100mm VAS: fatigue= no problem-major problem, High=bad  
NotesAuthors state positive mood measured by POMS vigor - it has 2 subscales: vigor/energy and fatigue. They measure mood so vigour is about feeling full of pep (energy)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"randomly assigned" but no further details given
Allocation concealment (selection bias)Low risk"participants were given envelopes containing instructions that randomly assigned them to one of the three conditions"
Blinding (performance bias and detection bias)
All outcomes
High riskexperimenter/raters unaware of arm assignment, not possible to blind participants
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk2 participants did not complete due to time constraints: not clear how their results were handled
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasLow riskNo evidence of other bias identified

Danoff-Burg 2006 - II

MethodsRCT: 3 arms
ParticipantsRA/Systemic Lupus Erythematosus (SLE), able to write for 20 minutes in English
InterventionsExpressive writing: encouraged participants to express their "deepest thoughts and feelings" about their experience with RA/SLE

Benefit finding: focus on "any positive thoughts and feelings" regarding their illness experience of RA/SLE

ALL arms had 3 week intervention, with 4 separate writing sessions within the 3-week period. Participants wrote alone in a private room in the laboratory for 20 minutes in accordance with their assigned instructions.
Outcomes

Primary: not stated

Relevant outcomes: Disability (HAQ), depression (CES-D), pain (VAS), anxiety (STAI

Other: Profile of Mood States (POMS)

ExclusionsNone stated
Fatigue outcomesa) POMS Vigor 0-32, high=good
b) 100mm VAS: fatigue= no problem-major problem, High=bad  
NotesAuthors state positive mood measured by POMS vigor - it has 2 subscales: vigor/energy and fatigue. They measure mood so vigour is about feeling full of pep (energy)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"randomly assigned" but no further details given
Allocation concealment (selection bias)Low risk"participants were given envelopes containing instructions that randomly assigned them to one of the three conditions"
Blinding (performance bias and detection bias)
All outcomes
High riskexperimenter/raters unaware of arm assignment, not possible to blind participants
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk2 participants did not complete due to time constraints: not clear how their results were handled
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasLow riskNo evidence of other bias identified

Das Gupta 2009

MethodsRCT: 2 arms
ParticipantsRA, disease duration >6 months, DAS 28 ≥3.2
InterventionsMain text indicates: 25mg indomethacin plus 3g omega-3 fatty acid. Abstract indicates: 75mg of indomethacin. Author contacted for clarification but no response received.
Outcomes

Primary outcome not identified

Relevant measures: disability (HAQ), tender joint count, swollen joint count, pain

Other: disease activity (DAS28), duration of morning stiffness, grip strength, ESR, health-related quality of life (SF-36)

ExclusionsMedical diseases including metabolic, endocrine, hepatic, renal, haematological, pulmonary, cardiovascular, or any other disease or condition that required active medical attention
Fatigue outcomesSF-36 vitality, range of scale 0-100, High = good
Notes

1. Abstract indicates 75mg of indomethacin but main text suggests 25mg

2. No mention of SF-36 in methods but results reported

3. SDs for change scores not provided

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details provided
Allocation concealment (selection bias)Unclear riskNo details provided
Blinding (performance bias and detection bias)
All outcomes
High riskParticipants in each arm received a different number of tablets
Incomplete outcome data (attrition bias)
All outcomes
High riskReasons for dropout not reported, no mention of how missing data were handled
Selective reporting (reporting bias)High riskSF-36 not listed in methods but results provided
Other biasHigh riskNo details of demographic information including disease duration and gender; possible errors in manuscript presentation, no information on adverse effects

Evans 2012

MethodsRandomised wait list control: 2 arms
ParticipantsRA for ≥ 6 months, age 16-35 years, stable medication for ≥ 4 weeks, ability to provide written informed consent, speak and understand English
InterventionsIvengar yoga with up to 7 people per class, lead by an experienced teacher and assisted by at least one junior teacher. 6 weeks (twice per week) for 1.5 hours per session (18 hours total)
Outcomes

Primary: not stated

Relevant outcomes: adverse events, Pain (pain disability index), Disability (HAQ), Anxiety and Depression (Brief Symptom Inventory)

Other: QoL (SF-36), disease activity (DAS), RA symptoms (Global Improvement scale), chronic pain acceptance, mindfulness, arthritis self-efficacy

ExclusionsPregnant, recently experienced an injury, history of drug or alcohol abuse, on any experimental medications in the previous 6 months
Fatigue outcomesSF-36 and FACIT-F
NotesStudy details obtained from unpublished report
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk'randomized in blocks' but no details of sequence generation
Allocation concealment (selection bias)Unclear risk‘randomised to either yoga or wait list control’ with no details of allocation concealment provided
Blinding (performance bias and detection bias)
All outcomes
High risk‘Principal investigators were blinded to participant randomization during the study process.’ No details provided for participant blinding or blinding of outcome assessors
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Selective reporting (reporting bias)Low risk 
Other biasHigh riskWait list control design may have biased participants. Statistically significant difference between arms in time since diagnosis

Evers 2002

MethodsRCT: 2 arms
ParticipantsACR criteria for RA, ≥18 years, disease duration <8 years, screened as "at risk" i.e. high levels of negative mood/anxiety, helplessness and lower acceptance
InterventionsTailored Cognitive Behavioural Therapy (CBT): 2/4 possible treatment models chosen based on patient priorities (pain and functional disability; fatigue; negative mood; social relationships). Homework assignments 30 minutes/day
Outcomes

Primary outcomes: physical, psychological and social functioning

Relevant secondary: functional disability (Impact of Rheumatic Diseases on General Health and Lifestyle - IRLG), pain (IRGL-pain scale), anxiety (IRLG - anxiety scale), depression (Beck Depression Inventory)

Others: disease activity (DAS: ESR and clinical joint score); negative mood; social function; illness cognition questionnaire - helplessness and acceptance; Utrechtse Coping Lijst; Pain Coping inventory; problem focusing scale; avoidance scale; compliance with RA medication

ExclusionsCo-morbidities e.g. malignancy, cardiac, respiratory, hepatic and renal problems that may affect CBT
Fatigue outcomesChecklist Individual Strengths (CIS) Fatigue Scale, 8 items, 1=True -> 7=Not true measures level of fatigue over previous 2 weeks, High=high fatigue
NotesGender - Table 1 does not state if % refer to women, but it is confirmed in text
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPreviously determined pattern of random numbers
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
High riskNo blinding of participants was reported and the nature of the intervention indicates that blinding was not undertaken
Incomplete outcome data (attrition bias)
All outcomes
Low risk"All analyses were conducted with completers as well as with intention-to-treat (ITT) analyses, using the last observation carried forward method"
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasLow riskITT and analysis of completers revealed same result. Differences between arms at baseline accounted for in analysis

Furst 1987

MethodsRCT: 2 arms
Participants18 years or over, RA diagnosis (ARA) for a minimum of 1 year, not hospitalised, permission to participate from general practitioner
InterventionsNew National Institutes of Health (NIH) Energy Conservation (EC) program: patient workbook: body position, rest, activity analysis and joint protection with didactic information, illustrations, practice assignments and self-evaluation.  Uses visual learning through text/illustrations, auditory learning through discussion with instructor, group and family. Homework assignments to reinforce learning
Outcomes

Primary outcome: not stated

Relevant outcomes: disability (HAQ), pain (HAQ VAS/Activity Record - ACTRE)

Other outcomes: psychosocial adjustment to illness (PAIS), knowledge (T/F questionnaire), disease activity (Richey-Camp Articular Index), Occupational Questionnaire adapted to measure behavioural objectives resulted in NIH Activity Record (ACTRE): log of activities for each 1/2hr of day over 2 days. Pain, fatigue, rest and PA measured as % of waking hours

ExclusionsInpatients, wheelchair-bound, temporary mobility limitations, currently receiving EC training
Fatigue outcomesa) VAS (added to HAQ), possible range 0-3, high=bad    b) ACTRE, During this time (activity) I felt fatigue 1=Not at all, 2=Very little, 3=Some, 4=A lot  per half hour, high=bad
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"pre-randomised treatment assignment lists for each centre were generated by computer"
Allocation concealment (selection bias)Low risk"randomly assigned to experimental or control groups". Patient ID numbers keyed to the centres
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
High riskPost-test data not provided. No mention of participants who left the study early. No 9 month data available
Selective reporting (reporting bias)High riskFull results not reported for all measures
Other biasHigh riskNot clear who delivered the interventions or performed the outcome measures. Number of sessions attended and adherence not reported. ACTRE was not a validated measure

Giraudet-Le-Quintrec 2007

MethodsRCT: 2 arms
ParticipantsRA
InterventionsBoth arms received 2 information leaflets written by the research team

Interactive multi-disciplinary education program plus usual medical care: information on the disease, treatment, diet, coping strategies, relaxation, exercise program to be followed at home. Self-efficacy principles to reduce pain and stress at home, behaviour modification techniques to change behaviours/improve quality of life by modifying psychological and social contacts
Outcomes

Primary outcome: health and functional status (HAQ)

Relevant secondary: Anxiety and Depression (Hospital Anxiety and Depression Scale - HADS)

Other: disease activity (DAS28), Arthritis Helplessness Index (AHI) score for Coping, Quality of life (EMIR17: score for the short form of the Arthritis Impact Measurement Scale - AIMS2), physical activity (Baecke questionnaire), drug compliance, satisfaction with the program, exercise and leisure physical activity compliance

ExclusionsJuvenile chronic arthritis, Steinbrocker class 4, pregnancy, RA flare, patient unable to understand information 
Fatigue outcomesFACIT-F, high=bad
Notes Mayoux-Benhamou is further reference report
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The allocation sequence was generated by randomly placing thoroughly shuffled marked cards into sequentially numbered sealed, opaque envelopes. This process was carried out by a statistics assistant not involved in the trial"
Allocation concealment (selection bias)Low risk"The allocation sequence was generated by randomly placing thoroughly shuffled marked cards into sequentially numbered sealed, opaque envelopes. This process was carried out by a statistics assistant not involved in the trial"
Blinding (performance bias and detection bias)
All outcomes
High risk12-month evaluation performed by 3 independent rheumatologists blind to arm allocation, not possible to blind participants
Incomplete outcome data (attrition bias)
All outcomes
Low risk"When possible (i.e. at least an available baseline value for the outcome) we handled missing data by the last observation carried forward method"
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasLow riskNo evidence of other bias identified

Hakkinen 2003

MethodsRCT: 2 arms
ParticipantsRecent-onset RA
(ACR 1987 criteria)
InterventionsIndividually designed home based dynamic strength training program. A physiotherapist initially guided the program during a 5 day inpatient period. Strength training included all the main muscle groups using dumb bells and elastic bands. Intensity was re-evaluated every 6 months
Outcomes

Primary outcome: functional capacity (Valpar whole body range of motion work sample and the HAQ)

Relevant secondary: Pain during transfers

Other: muscle strength, physical loading of work, disease activity (ESR, Ritchie index, Larsen score, pain), Transfer time

ExclusionsNone stated
Fatigue outcomes100mm VAS during Valpar transfers, 0-100mm, high=bad
NotesPossible contamination: control arm instructed to carry out exercises without any additional resistance and to continue recreational exercise with the exception of strength training. However, the only monitoring of this was self-report diaries and it is therefore possible that the control arm undertook resistance training. It is also possible that the intervention arm did not carry out the exercises at the intensity prescribed.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation performed using clusters of 4 stratified by age and sex but does not state how the sequence was generated
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention to treat
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasLow riskNo evidence of other bias identified

Hakkinen 2003-II

MethodsRCT: 2 arms
ParticipantsRecent-onset RA
(ACR 1987 criteria)
InterventionsIndividually designed home based dynamic strength training program. A physiotherapist initially guided the program during a 5 day inpatient period. Strength training included all the main muscle groups using dumb bells and elastic bands. Intensity was re-evaluated every 6 months
Outcomes

Primary outcome: functional capacity (Valpar whole body range of motion work sample and the HAQ)

Relevant secondary: Pain during transfers

Other: muscle strength, physical loading of work, disease activity (ESR, Ritchie index, Larsen score, pain), Transfer time

ExclusionsNone stated
Fatigue outcomes100mm VAS during Valpar transfers, 0-100mm, high=bad
NotesPossible contamination: control arm instructed to carry out exercises without any additional resistance and to continue recreational exercise with the exception of strength training. However, the only monitoring of this was self-report diaries and it is therefore possible that the control arm undertook resistance training. It is also possible that the intervention arm did not carry out the exercises at the intensity prescribed.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation performed using clusters of 4 stratified by age and sex but does not state how the sequence was generated
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention to treat
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasLow riskNo evidence of other bias identified

Hammond 2008

MethodsRCT: 2 arms
Participants≥18 years, RA or inflammatory arthritis. Psoriatic arthritis patients could also attend
InterventionsLifestyle Management for Arthritis Programme (LMAP): delivery by 3 therapists (2 occupational therapists and 1 physiotherapist) who had attended a training course and were observed with feedback to standardise delivery. Modules for patients = Looking after joints and keeping mobile and managing pain/mood. Modules involved self-monitoring, skills training, goal setting and action planning for home activity/exercise programmes
Outcomes

Primary outcome = Change in pain scores at 12 months

Relevant secondary: disability (modified HAQ)

Others: perceived health (very bad to very well), early morning stiffness, RA self-efficacy, arthritis self-efficacy scale, Arthritis Helplessness Index, self-management (Arthritis Stages of Change), visits to general practitioner over the past 6 months, medication 

ExclusionsSevere psychological difficulties/receiving mental health care, medical condition preventing safe exercise, previous education programme HAQ >2 indicating severe functional problems
Fatigue outcomesVAS: 100mm, No problem-major problem, high=bad
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomised by a research administrator to the modular or standard programme using computer-generated random numbers"
Allocation concealment (selection bias)Low risk"Pre-prepared sealed, opaque, numbered envelopes"
Blinding (performance bias and detection bias)
All outcomes
High riskNot possible. Participants could not be blinded to programme allocation but programme differences were not discussed. Outcomes were self-report questionnaires
Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat analysis
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasLow riskNo evidence of other bias identified

Harkcom 1985

MethodsRCT: 4 arms
ParticipantsRA
InterventionsA: Bicycle ergometry at 70% HRmax. 5 minute bouts of exercise separated by 1 minute rest periods. Progressed to 15 minutes of exercise by week 6

B: Bicycle ergometry at 70% HRmax. 5 minute bouts of exercise separated by 1 minute rest periods. Progressed to 25 minutes of exercise by week 6

C: Bicycle ergometry at 70% HRmax. 5 minute bouts of exercise separated by 1 minute rest periods. Progressed to 35 minutes of exercise by week 6
Outcomes

Primary outcome: not stated

Relevant outcomes: patient perceptions of changes in amount of joint pain and tolerance of joint pain

Other: morning stiffness, sleep patterns, self care, ambulation, activities of daily living. Global assessment: patient perceptions of changes in strength, ability to do housework, participation in social activities, overall mood. Grip strength, 50 foot walk time, muscle strength (knee flexors and extensors, joint evaluation. Exercise tolerance, aerobic capacity

ExclusionsNone stated
Fatigue outcomesa) Perception of change in fatigue, Worse-same-better-much better

b) Time to fatigue during exercise - BUT this was physiological fatigue
NotesSample size too small for statistical test, possible arm contamination - control arm may have exercised
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated
Allocation concealment (selection bias)Low risk"Patients independently chose an exercise time slot convenient for them...without knowledge of the protocol to which they would be assigned. The 4 different protocols were, in turn, randomly allocated to these time slots"
Blinding (performance bias and detection bias)
All outcomes
High riskNot possible for participants
Incomplete outcome data (attrition bias)
All outcomes
High riskNo information on missing data for 3 participants who dropped out
Selective reporting (reporting bias)High riskNo control data for fatigue. Exercise arms are combined and data are not reported in sufficient detail
Other biasHigh riskSample size too small for the statistical tests performed. No control data. Possible contamination if patients in the control arm chose to exercise

Helliwell 1999

MethodsRCT: 2 arms
ParticipantsRA (1987 ARA criteria) for less than 5 years. Able to read and speak English
InterventionsEducation classes took place over 4 weeks in 4 afternoon sessions lasting 2 hours. Format was a talk from a non-medical health professional, a discussion period and distribution of supporting literature. Content: pathophysiology of RA, drug treatments, local treatments, mechanisms and control of pain, stress, exercise and rest, joint protection, task allocation, splinting and assistive equipment.
Outcomes

Primary: Radiological damage (Larsen score of hand and wrist)

Relevant Secondary: disability (HAQ)

Other: Quality of life (SF-36), patient knowledge questionnaire, compliance questionnaire, Ritchie articular index, plasma viscosity, admission and clinic attendance, drug consumption and changes

ExclusionsNone stated
Fatigue outcomesSF36 Vitality, High=good
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk‘Randomization codes were taken from a table of random numbers...’
Allocation concealment (selection bias)Low risk‘...concealed in consecutive, numbered, sealed envelopes.’
Blinding (performance bias and detection bias)
All outcomes
High riskx-rays were blinded and assessed by an independent person but there was no blinding of participants and blinding of personnel was not detailed
Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention to treat
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasHigh riskNo attention control arm and no details of control arm in methods

Hewlett 2011

MethodsRCT: 2 arm
ParticipantsRA, scoring ≥6 on a VAS for fatigue during the past week
InterventionsCBT for fatigue self-management. Co-delivered by a clinical psychologist and OT. 6x2hour sessions during weeks 1-6 and a 1 hour consolidation session at week 14. Thoughts, feelings and behaviours related to fatigue were addressed using reflective questioning and guided discovery.  Problem solving, goal setting, self monitoring of rest/activity and activity management to improve well-being
Outcomes

Primary: Fatigue (MAF and VAS)

Relevant Secondary: pain (VAS), disability (HAQ), anxiety (HADS), depression (HADS)

Other: fatigue severity (VAS), fatigue coping (VAS), disease activity (VAS), personal impact (HAQ), QoL (RA QoL scale), helplessness (Arthritis Helplessness Index), self-efficacy (RA self-efficacy scale), sleep quality (binary scale)

ExclusionsChange in disease modifying drugs or biological agents in the previous 24 weeks or glucocorticoids in the previous 6 weeks
Fatigue outcomesMAF and VAS
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated random numbers
Allocation concealment (selection bias)Low riskProject managers emailed participant codes to an epidemiologist who performed randomisation off site
Blinding (performance bias and detection bias)
All outcomes
High risk'It was not possible to blind participants and staff, but self report measures were analysed blind to arm allocation.'
Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat analysis
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasLow riskNo evidence of other bias identified

Huffstutter 2007

MethodsRCT: 2 arms
ParticipantsOver 18 years; capable of reading, understanding, and providing written informed consent forms; diagnosed with active RA; disease severe enough to warrant a visit to their rheumatologist at least every 3 months
Interventions

During the first 6 months of study participation (pre-randomisation), ALL enrolled patients and their physicians entered data into the Electronic Data Capture System at each visit; however, Health Tracker (HT) reports summarizing the patients’ and physicians’ assessments of the first 6 months of visits were not available to any patients or physicians.

For intervention arm only: Health Tracker (HT) reports integrated and summarized each patients data generated at specific study visits occurring 6 to 12 months after study entry, including graphical displays of the number of patient-defined painful joints, Health Assessment Questionnaire (HAQ) scores, Short Form (SF)-12 scores, physician and patient global assessment scores, and anti-rheumatic medications over time.

Outcomes

Primary outcomes: Patients overall satisfaction with 8 aspects of their care: VAS 0 cm (completely unsatisfied) to 10 cm (completely satisfied). Physicians: 6-item patient-physician interaction questionnaire using a VAS (lower scores = easier interactions)

Relevant secondary: pain (VAS), disability (HAQ), patients self-evaluated painful joints on a joint mannequin diagram in EDCS, and a trained assessor examined patients and separately entered the painful and swollen joint count in the EDCS.

Other: Global disease assessments by the patient and the physician. Health-related quality of life (SF-12)

ExclusionsCurrently receiving investigational drugs or participating in other clinical trials or safety registries for RA or RA-related therapies
Fatigue outcomesVAS, no fatigue to fatigue is a major problem/very severe, high=bad
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details
Allocation concealment (selection bias)Unclear riskNo details
Blinding (performance bias and detection bias)
All outcomes
High riskParticipants were aware of the group allocation due to the nature of the intervention
Incomplete outcome data (attrition bias)
All outcomes
High riskNo mention of how missing participants' data were handled
Selective reporting (reporting bias)Unclear riskFatigue VAS data not reported in published paper
Other biasUnclear riskRandomised at 6 months but 0 months baseline measure used

Laforest 2008

MethodsRCT: 2 arms
ParticipantsHousebound (not leaving home independently more than twice a month), ≥50 years; reporting moderate to severe pain; suffering from OA or RA, reporting difficulties in performing domestic or daily living activities, able to speak English or French
InterventionsWeekly 1-hr individual home visits by a health care professional over 6 weeks. Participants explore themes of: (a) their life with arthritis, (b) physical and relaxation exercises, (c) managing pain and stiffness, (d) maintaining a positive attitude, (e) energy management, and (f) partnerships with health professionals and creative problem solving. Each session reviews previously discussed topics, explores a new theme, formulates a personal contract (i.e., defining an objective that is meaningful to the person and an action plan to meet it), and time for discussion and reflection. Session 1 planned to be 1.5 hours long, with subsequent sessions lasting 1 hour
Outcomes

Primary outcome: pain

Relevant secondary: depression (CES-D)

Others: Western Ontario and McMaster Universities Arthritis Index (functional limitations/stiffness), Arthritis Helplessness Index-brief, 4-item coping, arthritis self-efficacy scale, outcome expectations, frequency of physical/social activities, social life satisfaction 

ExclusionsPolymyalgia, recent health problems requiring rehabilitation services, cognitive problems, or previous participation in a similar intervention
Fatigue outcomesVAS: 100mm, No fatigue-fatigue as bad as it can be, high=bad
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The randomization procedure used a list of numbers that predetermined group allocation according to the number of participants required in each group"
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
High risk"None of the interviewers were involved in the administration of the intervention and they were blind to participants' group assignment" BUT "some interviewers may have become aware of the assignment of participants to the experimental or control conditions during follow-up interviews"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot stated
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasHigh riskNo details of control arm

Lorig 2005

MethodsRCT: 2 arms
ParticipantsA diagnosis of any rheumatic condition supplied by physician, ≥18 years 
InterventionsPrograms held in community locations led by a pair of trained peer leaders, one/both have a rheumatic condition. Each program is attended by 10-15 individuals with arthritis as well as some participants' significant others
Outcomes

Primary outcome: Pain was used as the basis of the sample size calculation

Relevant secondary: disability (Health Assessment Instrument); Visual Numeric Pain

Other: Health Distress (worry/concern caused by chronic illness, 5 items); Self-Rated Global Health; Activity Limitations; number of times/week individuals practice mental stress management and relaxation techniques; self-reported exercise; self-efficacy for managing chronic disease; physician visits in past 4 month; hospitalizations in past 4 months

ExclusionsPrevious participation in the Arthritis Self-Management Program or the Chronic Disease Self-Management Program
Fatigue outcomesVNS for fatigue, probably no fatigue to worst fatigue imaginable (from Ref 25), high=bad
NotesCo-morbidities = 65.7% IV, 75.4% Ctrl
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"All participants were randomized into 2 groups using random number charts"
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Low risk"Investigators were blinded to intervention assignment", self-report measures used
Incomplete outcome data (attrition bias)
All outcomes
Low riskAnalyses re-run with intention to treat and all missing data replaced by baseline values
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasHigh riskPossible contamination as recruited from Arthritis Foundation groups so patients randomized to different arms could have met regularly during the year

Lorig 2008

MethodsRCT: 2 arms
ParticipantsRA/osteoarthritis/fibromyalgia - self-report, ≥18 years, no previous Arthritis Self-Management Program participation, access to computer/email, agreement to 6 week commitment
Interventions25 patients per workshop, interactive web-based programme with 11 topics including bulletin board discussion, diaries, self-tests, arthritis handbook, online questionnaire. Aim=reduce pain and improve function
Outcomes

Primary outcome: Pain and function

Relevant secondary:disability (HQAQ-8 item)

Other: health distress, self-rated global health, disease impact (Activities Limitation Scale), health behaviour (stretching/strengthening, aerobic exercise, cognitive symptom management techniques, healthcare provider communication techniques, self-report outpatient visits), Arthritis Self-Efficacy Scale

ExclusionsActive cancer treatment in previous year
Fatigue outcomesVisual Numeric Scale 0-10, high=bad
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details
Allocation concealment (selection bias)Unclear riskNo details
Blinding (performance bias and detection bias)
All outcomes
High riskParticipants were aware of arm allocation due to the nature of the intervention
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing data collected by phone, checked for differences in completers/non-completers at baseline
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasLow riskNo evidence of other bias identified

Lumley 2011-I

MethodsRCT: 2 x 2 factorial design
ParticipantsAdults meeting 1987 ACR criteria, reported pain or morning stiffness during the week prior to screening
Interventions

Written emotional disclosure: one week duration, 4 writing sessions, blank journal for daily writing with specific instructions, intimal 20 minutes completed in clinic followed by 3 writing sessions at home for 20 minutes each. Participants identified a stressful life event to write about including thoughts and feelings about the event, meaning and effect upon beliefs or health and learning relating to coping that occurred as a result of the event.

 

Coping skills training: one session per week for 8 weeks individually with an advanced doctoral student or post doctoral fellow in clinical psychology for 75 minutes per session. Sessions were face to face where possible although some were carried out by phone. Therapist training consisted of a 2 day workshop. Training focused upon various cognitive behavioural skills.  Included education on gate control theory of pain, muscle relaxation, assertive communication skills, cognitive restructuring, activity-rest cycling, distraction, problem solving, relapse prevention.

Outcomes

Primary outcome: Disease activity (physician completed VAS) and pain (AIMS-2)

Relevant secondary: physical disability (AIMS-2), affective disturbance (AIMS-2)

Other: walking speed (timed 50ft walk), inflammation (C-reactive protein), intervention credibility (credibility scale)

ExclusionsOther autoimmune disorder, another disease that seriously affected function, illiterate or cognitively impaired, were in a formal behavioural pain management programme, had experienced a major stressful life change in the previous 6 months, unable to write or walk
Fatigue outcomesDaily diary NRS
NotesMajority of data were obtained directly from the author and were unpublished. Fatigue data were only available for the main effects RCT, that is: 1) all patients who undertook Written Emotional Disclosure versus Control Writing (irrespective of later training arms) and 2) all patients who undertook Coping Skills Training versus Education alone (irrespective of preceding writing arm)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk‘A person independent of the study staff used randomization software to develop the condition assignments’. Stratified by study site, medication class. Randomisation was done in blocks of 8, to one of 2 writing conditions followed by one of 2 training conditions
Allocation concealment (selection bias)Unclear risk‘assignments were sealed in envelopes’  does not state that they were opaque
Blinding (performance bias and detection bias)
All outcomes
High riskParticipants and study personnel were not blind to the interventions. There was blinded assessment of disease activity but the other measures were participant self-report
Incomplete outcome data (attrition bias)
All outcomes
Low risk'All analyses were conducted on the intent-to-treat sample of all 264 randomized participants. This is done by default in HLM, which estimates missing values; but for the ANCOVAs, we replaced those few missing values with the last available value (in most cases, using the baseline value for missing follow-up data).'
Selective reporting (reporting bias)Unclear riskNo daily outcome data were provided for fatigue, pain and positive and negative mood; states this will be presented in a separate paper
Other biasLow riskNo evidence of other bias identified

Lumley 2011-II

MethodsRCT: 2 x 2 factorial design
ParticipantsAdults meeting 1987 ACR criteria, reported pain or morning stiffness during the week prior to screening
Interventions

Written emotional disclosure: one week duration, 4 writing sessions, blank journal for daily writing with specific instructions, intimal 20 minutes completed in clinic followed by 3 writing sessions at home for 20 minutes each. Participants identified a stressful life event to write about including thoughts and feelings about the event, meaning and effect upon beliefs or health and learning relating to coping that occurred as a result of the event.

 

Coping skills training: one session per week for 8 weeks individually with an advanced doctoral student or post doctoral fellow in clinical psychology for 75 minutes per session. Sessions were face to face where possible although some were carried out by phone. Therapist training consisted of a 2 day workshop. Training focused upon various cognitive behavioural skills. Included education on gate control theory of pain, muscle relaxation, assertive communication skills, cognitive restructuring, activity-rest cycling, distraction, problem solving, relapse prevention.

Outcomes

Primary outcome: Disease activity (physician completed VAS) and pain (AIMS-2)

Relevant secondary: physical disability (AIMS-2), affective disturbance (AIMS-2)

Other: walking speed (timed 50ft walk), inflammation (C-reactive protein), intervention credibility (credibility scale)

ExclusionsOther autoimmune disorder, another disease that seriously affected function, illiterate or cognitively impaired, were in a formal behavioural pain management programme, had experienced a major stressful life change in the previous 6 months, unable to write or walk
Fatigue outcomesdaily diary NRS
NotesMajority of data were obtained directly from the author and were unpublished. Fatigue data were only available for the main effects RCT, that is: 1) all patients who undertook Written Emotional Disclosure versus Control Writing (irrespective of later training arms) and 2) all patients who undertook Coping Skills Training versus Education alone (irrespective of preceding writing arm)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk‘A person independent of the study staff used randomization software to develop the condition assignments’. Stratified by study site, medication class.  Randomisation was done in blocks of 8, to one of 2 writing conditions followed by one of 2 training conditions
Allocation concealment (selection bias)Unclear risk‘assignments were sealed in envelopes’  does not state that they were opaque
Blinding (performance bias and detection bias)
All outcomes
High riskParticipants and study personnel were not blind to the interventions. There was blinded assessment of disease activity but the other measures were participant self-report
Incomplete outcome data (attrition bias)
All outcomes
Low risk'All analyses were conducted on the intent-to-treat sample of all 264 randomized participants. This is done by default in HLM, which estimates missing values; but for the ANCOVAs, we replaced those few missing values with the last available value (in most cases, using the baseline value for missing follow-up data).'
Selective reporting (reporting bias)Unclear riskNo daily outcome data were provided for fatigue, pain and positive and negative mood; states this will be presented in a separate paper
Other biasLow riskNo evidence of other bias identified

Neuberger 2007 - I

MethodsRCT: 3 arms
Participants40-70 years, RA, able to read/speak English, ambulatory, rheumatologist approval to participate
InterventionsLow impact aerobics; warm up/low-impact/strength/cool down set to individual heart rate targets
Class - at a fitness centre
Home - video at home
Outcomes

Primary outcome: not specified

Relevant outcomes: Pain (McGill Pain Questionnaire), depression (CES-D), total joint count.

Other: ESR/CRP, grip strength, walk time, amount of exercise, aerobic fitness level, optimism (Life orientation test), exercise benefits/barriers, self-efficacy for exercise, confidence to exercise

ExclusionsArryhtmias, recent myocardial infarction, acute infection, uncontrolled metabolic disease, known electrolyte abnormalities, systolic blood pressure >200mgHg or diastolic >115mmHg, doing ≥30 minutes of exercise ≥3 times/week, history of fibromyalgia or severe chronic obstructive pulmonary disease, taking beta blockers or digitalis.
Fatigue outcomesa) MAF, range 3-50, high=bad
b) POMS, range 0-4
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"a priori list of randomly generated permutations of 3 numbers: class, home, control"
Allocation concealment (selection bias)Unclear riskNo details
Blinding (performance bias and detection bias)
All outcomes
High riskNot possible to blind participants or instructors but "trained assessors were blinded to group assignment"
Incomplete outcome data (attrition bias)
All outcomes
Low risk"intention to treat used in all analyses"
Selective reporting (reporting bias)High riskSocial support data collected but not reported
Other biasHigh riskNo data obtained on 62 withdrawals prior to T1 assessment therefore chance that more highly motivated participants were analysed. Exercise self-efficacy and confidence to exercise measures not tested in all RA patients

Neuberger 2007 - II

MethodsRCT: 3 arms
Participants40-70 years, RA, able to read/speak English, ambulatory, rheumatologist approval to participate
InterventionsLow impact aerobics; warm up/low-impact/strength/cool down set to individual heart rate targets
Class - at a fitness centre
Home - video at home
Outcomes

Primary outcome: not specified

Relevant outcomes: Pain (McGill Pain Questionnaire), depression (CES-D), total joint count

Other: ESR/CRP, grip strength, walk time, amount of exercise, aerobic fitness level, optimism (Life orientation test), exercise benefits/barriers, self-efficacy for exercise, confidence to exercise

ExclusionsArrhythmias, recent myocardial infarction, acute infection, uncontrolled metabolic disease, known electrolyte abnormalities, systolic blood pressure >200mgHg or diastolic >115mmHg, doing ≥30 minutes of exercise ≥3 times/week, history of fibromyalgia or severe chronic obstructive pulmonary disease, taking beta blockers or digitalis
Fatigue outcomesa) MAF, range 3-50, high=bad
b) POMS, range 0-4
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"a priori list of randomly generated permutations of 3 numbers: class, home, control"
Allocation concealment (selection bias)Unclear riskNo details
Blinding (performance bias and detection bias)
All outcomes
High riskNot possible to blind participants or instructors but "trained assessors were blinded to group assignment"
Incomplete outcome data (attrition bias)
All outcomes
Low risk"intention to treat used in all analyses"
Selective reporting (reporting bias)High riskSocial support data collected but not reported
Other biasHigh riskNo data obtained on 62 withdrawals prior to T1 assessment therefore chance that more highly motivated participants were analysed. Exercise self-efficacy and confidence to exercise measures not tested in all RA patients

Otter 2010

MethodsSingle blind comparison trial: 2 arms
ParticipantsRA, >18 years
InterventionsReflexology delivered by one of four reflexologists using a standard protocol to stimulate various reflexology points on the feet. Once per week for 6 weeks
Outcomes

Primary outcome: Fatigue (MAF)

Relevant outcomes: Foot Pain (Manchester Foot Pain Disability Questionnaire)

Other: Sleep (Insomnia Severity Index)

ExclusionsChanges in drug regime during the trial or in the previous 3 months, sensory neuropathy, current foot ulceration and/or infection and previous experience of reflexology or foot massage treatment
Fatigue outcomesMAF
NotesMajority of the study details were obtained from the author and were unpublished
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk‘The principle investigator allocated participants in a 1:1 ratio to receive either reflexology or foot massage’. No further details provided
Allocation concealment (selection bias)Unclear risk‘The principle investigator allocated participants in a 1:1 ratio to receive either reflexology or foot massage’. No further details provided
Blinding (performance bias and detection bias)
All outcomes
Low riskParitcipants were blind to the intervention and outcomes were self-report but the study personnel were not blind
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll data were obtained
Selective reporting (reporting bias)Low riskAll outcomes are presented
Other biasHigh riskGroups were not matched at baseline

Riemsma 2003 - I

MethodsRCT: 3 arms
ParticipantsMet at least 4 of the ACR criteria for RA. Significant other must be willing to participate
Interventions5 weekly 2 hour group sessions for 8 patients with significant other. 3 x 2 hour booster sessions after 3, 6 and 9 months. Each group had 2 trained leaders (nurses). Patients also received a programme book with information on the sessions, a self-help guide, brochures on RA and an audiotape with relaxation exercises. Programme included: contracting, goal setting and feedback; self-management and problem solving; information on RA and treatment; pain management and relaxation; physical exercises; coping with depression; and booster sessions
Outcomes

Primary outcomes: self-efficacy and health behaviour

Relevant secondary:

Other outcomes: disease activity (DAS28), health status (Dutch-AIMS2), social interactions, treatment credibility

ExclusionsResident in a nursing home, younger than 20 or older than 70 years
Fatigue outcomesVAS (tiredness on average during past wk due to arthritis), 0-100, high=bad
Notes42% of the group with significant others, 58% without significant others and 58% of the controls had no co-morbidities (53% total)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"randomly assigned " but no details
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumbers at each time point unclear
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasUnclear riskStatistically significant differences between arms at baseline for coping with pain and perceived problematic support

Riemsma 2003 - II

MethodsRCT: 3 arms
ParticipantsMet at least 4 of the ACR criteria for RA. Significant other must be willing to participate
Interventions5 weekly 2 hour group sessions for 8 patients with significant other. 3 x 2 hour booster sessions after 3, 6 and 9 months. Each group had 2 trained leaders (nurses).  Patients also received a programme book with information on the sessions, a self-help guide, brochures on RA and an audiotape with relaxation exercises. Programme included: contracting, goal setting and feedback; self-management and problem solving; information on RA and treatment; pain management and relaxation; physical exercises; coping with depression; and booster sessions
Outcomes

Primary outcomes: self-efficacy and health behaviour

Relevant secondary:

Other outcomes: disease activity (DAS28), health status (Dutch-AIMS2), social interactions, treatment credibility

ExclusionsResident in a nursing home, younger than 20 or older than 70 years
Fatigue outcomesVAS (tiredness on average during past wk due to arthritis), 0-100, high=bad
Notes42% of the group with significant others, 58% without significant others and 58% of the controls had no co-morbidities (53% total)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"randomly assigned " but no details
Allocation concealment (selection bias)Unclear riskNot stated
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumbers at each time point unclear
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasUnclear riskStatistically significant differences between arms at baseline for coping with pain and perceived problematic support

Skoldstam 2003

MethodsRCT: 2 arms
ParticipantsRA, diagnosed for at least 2 years, stable disease assessed by rheumatologist
InterventionsMediterranean Cretan diet (MD) including reduced fat, more green/black tea. Served by hospital for 3 weeks with 6 lessons about Mediterranean cooking from dietician. After rehabilitation same dietician was available weekly for telephone consultation and every third week for face to face consultation.
All MD patients got written instructions and recipes to facilitate the preparation of meals at home. The meals that both the MD and the control patients had to prepare at home were (a) every day breakfast and evening snacks; (b) meals for two weekends during rehabilitation; (c) every meal for the remaining nine weeks that followed rehabilitation. To enhance compliance, some food items were supplied free to the MD patients (olive oil, canola oil, liquid margarine, spreadable margarine, frozen vegetables, and tea).
Outcomes

Primary: disease activity (DAS 28), disability (Swedish HAQ), Health-related quality of life (SF-36 Swedish version), daily non-steroidal anti-inflammatory drugs (NSAIDs)

Relevant secondary:

Other: CRP, thrombocyte count, early morning stiffness, functional impairment, grip ability test

ExclusionsDisease-modifying anti-inflammatory drugs had to be unchanged for>3months, corticosteroids for >4 weeks, and NSAID for >10 days before beginning. Daily dose of oral corticosteroids could not exceed 12.5 mg of prednisolone. At baseline DAS28  >2.0 indicating active disease. Except for RA, the patients could have no other condition that demanded active medical attention. Patients who were vegetarians or who already lived on a Mediterranean-like diet were also excluded
Fatigue outcomesSF-36 Vitality, High=good
NotesCompliance data from Hagfors 2005a
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Stratified for gender, block randomisation with 2-6 per block"
Allocation concealment (selection bias)Unclear riskNo details
Blinding (performance bias and detection bias)
All outcomes
High riskDue to the nature of the intervention participants were not blinded
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk5 patients excluded - no details of how any missing data handled
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasHigh riskPossible contamination of control arm, violations of study protocol - injections. Arms not balanced at baseline. Statistically significant differences in diet between intervention and control arm but not clear how closely they adhered to the intervention. Diet is also all self-report questionnaires

Wang 2008

MethodsRCT: 2 arms
ParticipantsClass I and II RA, 18 and over
InterventionsTai Chi, one hour group sessions. Based on classical Yang style
Outcomes

Primary:  the proportion of participants who attained an ACR 20 response criterion at 12 weeks

Relevant secondary: tender and swollen joint scores; disability (HAQ); pain (VAS); depression (CES-D)

Other: Ritchie articular index, patient and physician VAS for disease severity, ESR, CRP, physical function, health-related quality of life (SF-36 and ED5D).

ExclusionsPrior experience of Tai Chi or other similar types of alternative and complementary therapy and/or were unwilling to abstain from Tai Chi (other than that provided in the study) until study completion, cardiovascular or other severe disease limitations precluding full participation, mini-mental status below 24, pregnant or breastfeeding, non-English speaking, participation in any other clinical trial in the previous 30 days.
Fatigue outcomesa) VAS: 0-100mm high=bad b) SF-36: 0-100 high=good
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomization assignments were made using computer-generated random numbers, in two groups of 10..."
Allocation concealment (selection bias)Low risk"...and were provided in sealed opaque envelopes upon agreement to participate"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details of participants or personnel, "physical examination and functional capacities were blindly assessed by the study rheumatologist and a physiologist"
Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention to treat
Selective reporting (reporting bias)Low riskNo evidence of selective reporting
Other biasHigh riskAt baseline the Tai Chi arm had statistically significantly worse HAQ scores and CRP. Two patients in the Tai Chi arm changed their medication during the study period

Zangi 2012

MethodsRCT: 2 arms
ParticipantsInflammatory arthritis diagnosed for ≥1 year; age 20-70 years
InterventionsVitality training programme: groups of 8-12 people. 10 sessions over 15 weeks initially with a booster at 6 months. 4.5 hours per session (49.5 hours in total). Included mindfulness-based exercises, creative exercises, reflection. Between sessions participants listened to a compact disc with mindfulness based exercises. Group facilitators were health professionals trained in mindfulness-based exercises
Outcomes

Primary: Psychological distress (General Health Questionnaire-20), self-efficacy (Arthritis Self-Efficacy Scale) and emotion focused coping (Emotional Approach Coping Scale)

Relevant secondary: Pain (NRS)

Other: patient reported disease activity, self care ability and overall well being (all by NRS)

ExclusionsInability to understand Norwegian
Fatigue outcomesNRS
NotesMajority of the published results reported were for all participants with inflammatory arthritis. Specific data for RA participants were unpublished and obtained from the study authors.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk‘A statistician generated randomization lists’ using specialist computer software ‘with blocks of 10 and 15 for each department to ensure approximately equal sample sizes.
Allocation concealment (selection bias)Low risk‘Participants were given consecutive numbers and a person not involved in the data collection or intervention allocated each participant to the corresponding numbers on the randomization list’.
Blinding (performance bias and detection bias)
All outcomes
High riskStudy personnel and participants were not blinded. ‘The persons conducting telephone interviews were blinded for group assignments, and participants were instructed not to discuss their intervention with the interviewer.’ ‘A blinded statistician conducted statistical analysis. The randomization code was not opened until the primary analyses were completed.’
Incomplete outcome data (attrition bias)
All outcomes
Low riskMixed-effects model
Selective reporting (reporting bias)Low riskAll outcomes were reported
Other biasHigh riskControl arm were advised that they could access the intervention at the end of the study which is likely to have raised expectations and hence bias

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Barlow 1998Not an RCT
Barlow 2000RA data not reported separately for RA participants
Barlow 2009Not an RCT
Behandling og traeningUnobtainable
Bhat 2008RA data not reported separately for RA participants
Bhat 2010Not an RCT
Callahan 2008RA data not reported separately for RA participants
Daltroy 1995RA data not reported separately for RA participants
de Buck 2005RA data not reported separately for RA participants
Evers 2005Not an RCT - summary report of several studies
Furst 2000No fatigue outcome measure
Goldbach-Mansky 2009No fatigue outcome measure
Hagfors 2003Not an RCT
Hagfors 2005Not an RCT
He 2008No fatigue outcome measure
Heiberg 2007Not an RCT
Jiang 2012No fatigue outcome measure
Kremer 1987Not an RCT
Lee 2006Not an RCT
MacDonald 1994No fatigue outcome measure
Minnock 2008Not an RCT
Mur 2002No fatigue outcome measure
Neuberger 1997Not an RCT
Nordemar 1981Not an RCT
Noreau 1995Not an RCT
O'Leary 1986No fatigue outcome measure
Pan 2009Not an RCT
Poulsen 1991No fatigue outcome measure
Rall 1996Not an RCT
Rauma 1993No fatigue outcome measure
Solomon 2002RA data not reported separately for RA participants
Song 2007No fatigue outcome measure
Stenstrom 1993No fatigue outcome measure
Stenstrom 1994No fatigue outcome measure
Stenstrom 1996RA data not reported separately for RA participants
Taibi 2009No fatigue outcome measure
Toirov 2010Not an RCT

Characteristics of studies awaiting assessment [ordered by study ID]

Berbert 2005

MethodsData query - still trying to contact authors
Participants 
Interventions 
Outcomes 
Notes 

Wiesenauer 1991

MethodsAwaiting translation
Participants 
Interventions 
Outcomes 
Notes 

Ancillary