Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn's disease

  • Review
  • Intervention

Authors


Abstract

Background

The anti-inflammatory effects of n-3 (omega-3 fatty acids, fish oil) have been suggested to be beneficial in chronic inflammatory disorders such as inflammatory bowel disease. This review is an update of a previously published Cochrane review.

Objectives

To systematically review the efficacy and safety of n-3 for maintenance of remission in Crohn's disease (CD).

Search methods

The following databases were searched from inception to November 2013 without language restriction: CENTRAL, MEDLINE, EMBASE, HealthSTAR, PubMed, and ACP journal club.

Selection criteria

Randomized placebo-controlled trials (RCT) of n-3 for maintenance of remission in CD were included. Studies must have enrolled patients of any age group, who were in remission at the time of recruitment, and were followed for at least six months. The intervention must have been fish oil or n-3 given in pre-defined dosage. Co-interventions were allowed only if they were balanced between the study groups.

Data collection and analysis

The primary outcome was the relapse rate and secondary outcomes included change in disease activity scores, time to first relapse and adverse events. Two independent investigators reviewed studies for eligibility, extracted the data and assessed study quality using the Cochrane risk of bias tool. The overall quality of the evidence supporting the primary and selected secondary outcomes was reassessed for the current update using the GRADE system. We used the RevMan software for analyses. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for dichotomous outcomes and the hazard ratio and 95% CI for time-to-event outcomes. Random-effects or fixed-effect models were used according to degree of heterogeneity and sensitivity analyses were performed in an attempt to explore possible sources of heterogeneity.

Main results

Six studies with a total of 1039 patients were eligible for inclusion. The two largest studies were rated as low risk of bias for all assessed items. Four studies were rated as unclear risk of bias for randomization and allocation concealment. Two studies were rated as high risk of bias for incomplete outcome data and selective reporting. There was a marginal significant benefit of n-3 therapy for maintenance of remission. Thirty-nine per cent of patients in the n-3 group relapsed at 12 months compared to 47% of placebo patients (6 studies, 1039 patients; RR 0.77, 95% CI 0.61 to 0.98). A GRADE analysis rated the overall quality of the evidence for the primary outcome (i.e. relapse) as very low due to unexplained heterogeneity (I2 = 58%), publication bias, and a high or unknown risk of bias in four studies in the pooled analysis. When two large studies at low risk of bias were considered the benefit was no longer statistically significant. Thirty-seven per cent of patients in the n-3 group relapsed at 12 months compared to 42% of placebo patients (2 studies, 738 patients; RR 0.88, 95% CI 0.74 to 1.05). No significant heterogeneity was identified for this pooled analysis ( I2 = 0%). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (294 events). No serious adverse events were recorded in any of the studies but in a pooled analyses there was a significantly higher rate of diarrhea (4 studies, 862 patients; RR 1.36 95% CI 1.01 to 1.84) and upper gastrointestinal tract symptoms (5 studies, 999 patients; RR 1.65, 95% CI 1.25 to 2.18) in the n-3 treatment group.

Authors' conclusions

Evidence from two large high quality studies suggests that omega 3 fatty acids are probably ineffective for maintenance of remission in CD. Omega 3 fatty acids appear to be safe although they may cause diarrhea and upper gastrointestinal tract symptoms.

Résumé scientifique

Acides gras oméga 3 (huile de poisson) pour le maintien de la rémission dans la maladie de Crohn

Contexte

Il a été suggéré que les effets anti-inflammatoires des n-3 (acides gras oméga-3, huile de poisson) pourraient être bénéfiques dans les troubles inflammatoires chroniques telles que les maladies inflammatoires de l'intestin. Cette revue est une mise à jour d'une revue Cochrane publiée précédemment.

Objectifs

Examiner systématiquement l'efficacité et l'innocuité des n-3 pour le maintien de la rémission dans la maladie de Crohn (MC).

Stratégie de recherche documentaire

Les bases de données suivantes ont été consultées depuis leur création jusqu'à novembre 2013, sans restriction de langue : CENTRAL, MEDLINE, EMBASE, HealthSTAR, PubMed et ACP journal club.

Critères de sélection

Les essais randomisés contrôlés par placebo (ECR) sur les n-3 pour le maintien de la rémission dans la MC ont été inclus. Les études devaient avoir recruté des patients de tout groupe d'âge, qui étaient en rémission lors du recrutement, et ont été suivis pendant au moins six mois. L'intervention devait administrer de l'huile de poisson ou des n-3 au dosage prédéfini. Les co-interventions étaient autorisées si elles était équilibrées entre les groupes d'étude.

Recueil et analyse des données

Le critère de jugement principal était le taux de rechute et les critères de jugement secondaires incluaient les changements dans les scores d'activité de la maladie, le délai avant la première récidive et les événements indésirables. Deux évaluateurs indépendants ont examiné l'éligibilité des études, extrait les données et évalué la qualité des études en utilisant l'outil Cochrane de risque de biais. La qualité globale des preuves étayant le critère de jugement principal et les critères secondaires sélectionnés a été réévaluée pour la présente mise à jour en utilisant le système GRADE. Nous avons utilisé le logiciel RevMan pour les analyses. Nous avons calculé le risque relatif (RR) et l'intervalle de confiance (IC) à 95 % correspondante pour les résultats dichotomiques et le rapport des risques instantanés (hazard ratio) avec IC à 95 % pour les critères de jugement du délai jusqu'à l'évènement. Les modèles à effets aléatoires ou à effets fixes ont été utilisés selon le degré d'hétérogénéité et des analyses de sensibilité ont été effectuées dans le but d'explorer de possibles sources d'hétérogénéité.

Résultats principaux

Six études portant sur un total de 1 039 patients ont été éligibles pour l'inclusion. Les deux plus grandes études ont été considérées comme présentant un faible risque de biais pour tous les éléments évalués. Quatre études ont été considérées à risque de biais incertain pour la randomisation et l'assignation secrète. Deux études ont été considérées comme étant à risque de biais élevé pour les données de résultat incomplètes et la notification sélective. Il y avait un effet bénéfique significatif marginal du traitement par n-3 pour le maintien de la rémission. Trente-neuf pour cent des patients dans le groupe n-3 avaient rechuté à 12 mois par rapport à 47 % des patients sous placebo (6 études, 1 039 patients ; RR 0,77, IC à 95 % 0,61 à 0,98). L'analyse GRADE a évalué la qualité globale des preuves pour le critère de jugement principal (rechute) comme très faible en raison d'hétérogénéité inexpliquée (I2 = 58 %), de biais de publication et d'un risque de biais élevé ou inconnu dans quatre études dans l'analyse combinée. Lorsque deux grandes études à faible risque de biais ont été prises en compte, le bénéfice n'était plus statistiquement significatif. Trente-sept pour cent des patients dans le groupe n-3 avaient rechuté à 12 mois par rapport à 42 % des patients sous placebo (2 études, 738 patients ; RR 0,88, IC à 95 % 0,74 à 1,05). Aucune hétérogénéité significative n'a été identifiée pour cette analyse combinée ( I2 = 0 %). L'analyse GRADE a indiqué que la qualité globale des preuves étayant ce critère de jugement était modérée en raison du petit nombre de données (294 événements). Aucun événement indésirable grave n'était rapporté dans aucune des études mais dans une analyse combinée il y avait un taux significativement plus élevé de diarrhée (4 études, 862 patients ; RR 1,36 IC à 95 % 1,01 à 1,84) et de symptômes du tractus gastro-intestinal supérieur (5 études, 999 patients ; RR 1,65, IC à 95 % 1,25 à 2,18) dans le groupe de traitement n-3.

Conclusions des auteurs

Les preuves issues de deux études de haute qualité à grande échelle suggèrent que les acides gras oméga 3 ne sont probablement pas efficaces pour le maintien de la rémission dans la MC. Les acides gras oméga 3 semblent être sans danger bien qu'ils puissent entraîner des diarrhées et des symptômes du tractus gastro-intestinal supérieur.

アブストラクト

クローン病の寛解維持に対するオメガ3脂肪酸(魚油)

背景

n-3(オメガ-3脂肪酸、魚油)の抗炎症作用について、炎症性腸疾患などの慢性炎症性疾患における有効性が示唆されてきている。本レビューは過去に発表されたコクラン・レビューの更新である。

目的

クローン病(CD)の寛解維持に対するn-3の有効性と安全性についてシステマティックに調査すること。

検索戦略

言語にかかわらず以下のデータベースを開始から2013年11月まで検索した。CENTRAL、MEDLINE、EMBASE、HealthSTAR、PubMed、およびACP journal club。

選択基準

CDの寛解維持におけるn-3についてのランダム化プラセボ対照比較試験(RCT)を選択した。研究は、募集時に寛解状態にあり、最低6カ月間追跡が行われた患者(全年齢群)が登録されていることを必須条件とした。魚油またはn-3を事前に定めた用量で投与する介入が行われていることを必須条件とした。研究群の間で均衡がとれている場合にのみ共介入を許容した。

データ収集と分析

主要アウトカムを再発率、副次的評価項目を疾患活動性スコアの変化、初回再発までの時間、および有害事象とした。2名の独立した研究者が研究の適格性を調査し、データを抽出し、コクランのバイアスのリスクツールを用いて、試験の質を評価した。主要アウトカムおよび選択した副次的評価項目に関するエビデンスの全般的な質について、GRADEシステムを用いた今回の更新で再評価した。RevManソフトウェアを用いて解析した。二値アウトカムに関するリスク比(RR)と95%信頼区間(CI)、およびアウトカムイベントまでの時間に関するハザード比と95%CIを算出した。異質性に合わせて変量効果モデルや固定効果モデルを用いた。また、考えられる異質性の原因を調べるために感度分析を行った。

主な結果

合計1039例を対象とした6件の研究を適格として選択した。規模が大きい2件の研究では、全評価項目のバイアスに関して低リスクと評価した。4件の研究では、ランダム化と割り付けのコンシールメント(隠蔵化)に関するバイアスのリスクを不明と評価した。2件の研究では、不十分なアウトカムデータと選択的な報告のバイアスに関して高リスクと評価した。寛解維持におけるn-3療法について、最低限の有意な効果がみられた。12カ月の時点で再発した患者は、n-3 群で39%であったのに対し、プラセボ群では47%であった(6件の研究、1039例;RR 0.77、95% CI 0.61~0.98)。GRADEシステムを使った解析によって、主要アウトカム(再発)に関するエビデンスの全般的な質はきわめて低いと評価した。その理由として、異質性に関する説明がないこと(I2 = 58%)、出版バイアス、プール解析における4件の研究のバイアスのリスクが高いまたは不明であることがあげられる。 バイアスのリスクが低く規模の大きな2件の研究について検討したところ、統計学的に有意な利益はなかった。12カ月の時点で再発した患者は、n-3 群で37%であったのに対し、プラセボ群では42%であった(2件の研究、738例; RR 0.88、95% CI 0.74~1.05)。本プール解析について有意な異質性は認められなかった( I2 = 0%)。 GRADEシステムを使った解析により、本アウトカムに関するエビデンスの全般的な質については、データが少ない(294件のイベント)ため、中等度であることが示された。重篤な有害事象を記録した研究はなかったが、プール解析ではn-3治療群で下痢(4件の研究、862例; RR 1.36 95%CI 1.01~1.84)、および上部消化管症状(5件の研究、999例;RR 1.65、95%CI 1.25~2.18)の発症率が有意に高かった。

著者の結論

規模が大きく良質な2件の研究のエビデンスでは、オメガ3脂肪酸はおそらくCDの寛解維持に対して効果がないことを示している。オメガ3脂肪酸は下痢や上部消化管症状を引き起こすことがあるが、安全であると考えられる。

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/)[2015.12.31]
《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

Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn's disease

Fish oil contains omega 3 fatty acids that may be beneficial in reducing inflammation, such as seen in the bowel of Crohn's disease patients. Randomized placebo-controlled studies that evaluated the effect of daily intake of capsules containing omega-3 fatty acids to maintain remission in Crohn's disease were reviewed. Six studies including 1039 patients were included in the review. A pooled analysis of six studies suggests a marginal benefit for omega 3 fatty acids over placebo (i.e. fake medicine) in preventing relapse of disease at one year. However, these results need to be interpreted with caution due to differences across the studies in terms of induction of remission regimens (e.g. surgical remission versus drug therapy) patients (e.g. adult versus pediatric patients) and medication regimens (e.g. some studies used different placebos), the possibility of publication bias (i.e. only studies with positive results are published) and low methodological quality in four studies in the pooled analysis. When the two largest and highest quality studies were pooled the results showed no benefit to omega-3 treatment over placebo. There were no serious side effects in any of the studies. Common side effects included unpleasant taste, bad breath, heartburn, nausea and diarrhea. Evidence from two large high quality studies suggests that omega 3 fatty acids are probably ineffective for maintenance of remission in CD. Omega 3 fatty acids appear to be safe although they may cause diarrhea and upper gastrointestinal tract symptoms.

Résumé simplifié

Acides gras oméga 3 (huile de poisson) pour le maintien de la rémission dans la maladie de Crohn

L'huile de poisson contient des acides gras oméga 3 qui peuvent être bénéfiques dans la réduction de l'inflammation, comme celle observée dans l'intestin des patients atteints de maladie de Crohn. Nous avons examiné les études randomisés contrôlés par placebo qui évaluaient l'effet de la prise quotidienne de gélules contenant des acides gras oméga-3 pour maintenir la rémission dans la maladie de Crohn. Six études portant sur 1 039 patients ont été incluses dans la revue. Une analyse combinée des six études suggère un bénéfice marginal des acides gras oméga 3 par rapport au placebo (médicament inactif) pour prévenir la récidive de la maladie à un an. Cependant, ces résultats doivent être interprétés avec prudence en raison des différences entre les études en termes de régimes d'induction de la rémission (par ex. rémission chirurgicale ou traitement médicamenteux), de patients (par ex. adultes ou patients pédiatriques) et de régimes médicamenteux (par ex. certaines études avaient utilisé des placebos différents), ainsi qu'en raison de la possibilité de biais de publication (par ex. seules les études ayant des résultats positifs sont publiées) et de la faible qualité méthodologique de quatre études dans l'analyse combinée. Lorsque les deux études les plus grandes et de la meilleure qualité ont été regroupées, les résultats n'ont montré aucun bénéfice au traitement par l'oméga-3 par rapport à un placebo. Il n'y avait aucun effet secondaire grave dans aucune des études. Les effets secondaires courants incluaient un goût désagréable, une mauvaise haleine, des brûlures d'estomac, des nausées et la diarrhée. Les preuves issues de deux études de haute qualité à grande échelle suggèrent que les acides gras oméga 3 ne sont probablement pas efficaces pour le maintien de la rémission dans la maladie de Crohn. Les acides gras oméga 3 semblent être sans danger bien qu'ils puissent entraîner des diarrhées et des symptômes de l'appareil gastro-intestinal supérieur.

Notes de traduction

Traduit par: French Cochrane Centre
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux; pour la France : Minist�re en charge de la Sant�

Laički sažetak

Omega-3 masne kiseline (riblje ulje) za održavanje remisije u Crohnovoj bolesti

Riblje ulje sadrži omega-3 masne kiseline koje možda mogu biti djelotvorne u smanjenju upale koje vidimo u crijevima kod pacijenata s Crohnovom bolesti. Pregledane su randomizirane i placebom kontrolirane studije koje procjenjuju učinak dnevnog unosa kapsula koje sadrže omega-3 masne kiseline na održavanje remisije kod Crohnove bolesti. U Cochrane sustavni pregled je uključeno šest studija, s 1039 pacijenata. Združene analize tih šest studija upućuju na graničnu korist omega-3 masnih kiselina u odnosu na placebo ( tj. lažni lijek) u prevenciji povratka bolesti nakon godine dana. Međutim, ti se rezultati moraju tumačiti s oprezom zbog razlika studija u uvjetima indukcije režima remisije (npr. kirurška remisija naspram terapije lijekom), različitih pacijenata ( npr. odrasli naspram djece) i različitih režima liječenja (npr. neke studija su rabile različite placebo pripravke), te mogućih pristranosti objavljivanja (npr. objavljene su samo studije s pozitivnim rezultatima) i niske kvalitete metodologije u četiri studije. Kad su zajedno analizirani podatci samo dvije najveće i kvalitetom najviše studije, rezultati nisu pokazali korist od omega-3 masnih kiselina u odnosu na placebo. Nisu opažene ozbiljne nuspojave ni u jednoj studiji. Česte nuspojave su uključivale neugodan okus, loš zadah, žgaravicu, mučninu i proljev. Dokazi iz dva velika i visokokvalitetna istraživanja upućuju da omega-3 masne kiseline vjerojatno nisu učinkovite za održavanje remisije Crohnove bolesti. Omega-3 masne kiseline čine se sigurnim u pogledu nuspojava, iako mogu uzrokovati proljev i simptome gornjega gastrointestinalnog trakta.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Anni Mikić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

平易な要約

クローン病の寛解維持に対するオメガ3脂肪酸(魚油)

魚油は、クローン病患者の腸でみられるような炎症を減らすのに有効と考えられているオメガ3脂肪酸を含有する。クローン病の寛解維持のため、オメガ-3脂肪酸を含むカプセルを毎日摂取した場合の効果を評価した、ランダム化プラセボ対照比較試験について調査した。本レビューでは、1039例を対象とした6件の研究を選択した。6件の研究のプール解析では、1年の時点での疾患の再発予防に対して、オメガ3脂肪酸にはプラセボ(偽薬)を上回る限界利益があることが示唆されている。しかし、これらの結果の解釈には注意を要する。その理由として、寛解導入レジメン(例:外科的寛解と薬物療法の比較)、患者(例:成人患者と小児患者の比較)、および投薬レジメン(例:複数の研究で異なるプラセボを使用していた)に関して研究間の相違があること、出版バイアスの可能性(好ましい結果が出た研究だけを発表する)、およびプール解析における4件の研究の方法論的な質が低いことがあげられる。もっとも良質で規模の大きな2件の研究について統合したところ、オメガ-3治療はプラセボを上回る利益を示さなかった。すべての研究で重篤な副作用はみられなかった。よくみられる副作用として、嫌な味、口臭、胸焼け、悪心、下痢などがある。規模が大きく良質な2件の研究のエビデンスでは、オメガ3脂肪酸はおそらくCDの寛解維持に対して効果がないことを示している。オメガ3脂肪酸は下痢や上部消化管症状を引き起こすことがあるが、安全であると考えられる。

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/)[2015.12.31]
《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. 
  1. 1 The control group risk estimate comes from the control arm of the included studies.
    2 Significant unexplained heterogeneity.
    3 Likely publication bias is indicated by the absence of negative small studies.
    4 Two of the studies in the analysis were at high risk of bias due to incomplete outcome data and selective reporting.
    5 Sparse data (374 events).
    6 Sparse data (294 events).
    7 Sparse data (144 events).
    8 Sparse data (167 events).

n-3 therapy compared with placebo for maintaining remission in CD

Patient or population: Crohn's disease patients in remission

Settings: adult and pediatric outpatient gastroenterology and IBD centers, single-center and multicenter; not stated in one study ( Belluzzi 1997).

Intervention: n-3 or fish oil capsules

Comparison: placebo capsules

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
placebo n-3 or fish oil capsules
Relapse rate at one year (all studies) Study population

RR 0.77

(0.61 to 0.98)

1039
(6 studies)
⊕⊝⊝⊝
very low 2,3,4
 
471 per 1000 1 363 per 1000
(287 to 462)
Relapse rate at one year (sensitivity analysis of Belluzi 1996) Study population RR 0.77 (0.64 to 0.93)904
(5 studies)
⊕⊝⊝⊝
very low 3,4,5
 
459 per 1000 353 per 1000
(294 to 462)
Relapse rate at one year (only EPIC studies) Study population RR 0.88 (0.74 to 1.05)738
(2 studies)
⊕⊕⊕⊝
moderate 6
Well-designed and implemented studies, larger than all other studies combined
424 per 1000 373 per 1000
(314 to 445)
Adverse events rate-Diarrhea Study population RR 1.36 (1.01 to 1.84)862
(4 studies)
⊕⊕⊕⊝
moderate 7
 
140 per 1000 190 per 1000
(141 to 258)
Adverse events rate- Upper GI (nausea, vomiting, halitosis, heartburn, dyspepsia, dysgeusia and bloating) Study population RR 1.98 (1.38 to 2.85)999
(5 studies)
⊕⊕⊕⊝
moderate 8
 
123 per 1000 244 per 1000
(170 to 351)
*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; RR: Risk Ratio;RD: Risk Difference;OR: Odds Ratio; HR: Hazard Ratio.
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

Crohn's disease
Crohn's disease (CD) is characterized by chronic intestinal inflammation causing a varying spectrum of clinical symptoms. Some patients have chronically active disease, while others have a pattern of clear exacerbations and remissions. It is currently hypothesized that chronic inflammation develops in genetically susceptible hosts in response to as yet unidentified environmental triggers, likely microbial in origin. No maintenance medication has been shown to be completely effective in preventing relapse, and thus prolonging remission intervals while minimizing adverse reactions has been the aim of treatment. Adherence to a low residue diet may reduce symptoms in patients with intestinal stenosis and administration of formulated food as the sole source of nutrition is efficacious in alleviating mucosal inflammation (Zachos 2007). Otherwise, no dietary restrictions or interventions have been convincingly shown to treat active CD or to prevent clinical exacerbation.

Omega-3 poly-unsaturated fatty acids (n-3)
Randomized controlled trials have suggested a positive effect of n-3 in various disease states, including cardiovascular, inflammatory, immunological, psychological, and neurological disorders (Akabas 2006; Belluzzi 2002; Ergas 2002; Hooper 2004; Ruxton 2004; Simopoulos 2002). The beneficial effects of n-3 are thought to be secondary to anti-inflammatory, antithrombotic, antiarrhythmic, hypolipidemic and vasodilatory properties. Omega-3 polyunsaturated fatty acids (n-3) are incorporated into the wall of inflammatory cells and decrease the concentration of arachidonic acid (C20:4, n-6). Arachidonic acid is the key substrate of cyclooxygenase and 5-lipoxygenase enzymes which produce proinflammatory cytokines (Hillier 1991). In this way, n-3 fatty acids reduce the production of leukotriene B4, thromboxane A2, prostaglandin E2, interleukin-1, interleukin-6 and tumor necrosis factor, and scavenge free radicals (Endres 1989; Fisher 1986; Kim 1996; Lee 1985; Simopoulos 2002).

Although n-3 can be obtained from various vegetables, the major source of n-3 is fish oil. The marine sources of n-3 include eicosapentanoic acid (EPA or 20:5), docosahexanoic acid (DHA, 22:6) and docosapentanoic acid (DPA, 22:5), which are the longer chain n-3 forms. Alpha linolenic acid (ALA, 18:3) is the shorter chain n-3 obtained from nuts and vegetable oils. Although an endogenous process exists whereby ALA can be partially converted to the effective longer chain n-3, there is debate about the effectiveness of this conversion (Arterburn 2006; Ruxton 2004).

n-3 and Crohn's disease
Studies on animal models and tissues of IBD patients have demonstrated the strong anti-inflammatory properties of n-3 (Nakazawa 2000; Vilaseca 1990). It has been proposed that a diet rich in fish oil protected the Japanese from IBD and now the rate of IBD is increasing due to dietary shift from n-3 to n-6 (Nakazawa 2000). Reports of n-3 use for maintaining remission in CD have been conflicting (MacLean 2005). Although n-3 has an excellent safety profile, when administered as raw fish oil it was shown to have troublesome adverse effects that reduced compliance. These adverse effects include unpleasant taste, halitosis, heartburn, nausea and diarrhea (Kim 1996; Lorenz 1989). Investigators have suggested the use of enteric coated capsules to improve compliance and absorption (Belluzzi 1994).

Importance of this review
Narrative reviews of fish oil in CD have reported conflicting conclusions, based on the same published studies (Belluzzi 2002; Endres 1999; Kim 1996; Nakazawa 2000; Simopoulos 2002). Our previous systematic review published in 2009 concluded that omega-3 fatty acids are probably ineffective for maintenance of remission in Crohn's disease (Turner 2009). In light of continued public interest in finding natural alternatives or adjuncts to current immunosuppressive therapies and the four years that have elapsed since the last literature search, we aimed to update our previous review.

Objectives

The primary objective of this study was to systematically review the effectiveness of fish oil or n-3 for maintaining remission in CD. A secondary objective was to evaluate the adverse events associated with fish oil or n-3 for maintaining remission in CD.

Methods

Criteria for considering studies for this review

Types of studies

Randomized placebo-controlled trials of fish oil or n-3 therapy administered for at least six months, reporting at least one of the primary or the secondary outcomes and published in any language, were included in this review. Studies published in an abstract form only were included if enough data were provided to assess the reported outcomes.

Types of participants

Crohn's disease patients (diagnosed using established criteria) who were in remission at the time of recruitment were included. We did not apply any age restrictions (both pediatric and adult patients were included). The following validated clinical indices could have been used to assess disease activity and remission: the Crohn's disease activity index (CDAI) (Best 1976), the pediatric Crohn's disease activity index (PCDAI) (Hyams 1991), the weighted pediatric Crohn's disease activity index (wPCDAI) and the other short versions (Turner 2012), and the Harvey-Bradshaw index (Harvey 1980). In practice, only the first two indices were used in the eligible studies.

Types of interventions

Trials were included if fish oil or n-3 supplementation was given in any form (capsule, enteric coated or liquid) but with a defined dose. Co-interventions were allowed only if they were balanced between the study groups. Studies in which the intervention group received diet enriched with fish products were excluded as the dose was not clear in these studies and other confounding variables could exist.

Types of outcome measures

Primary outcome
The primary outcome was the relapse rate during the observation time. Definitions of relapse were guided by the validated indices specified above.

Secondary outcome
The secondary outcomes were change in disease activity scores, time to first relapse and adverse events (diarrhea, nausea, vomiting, halitosis, heartburn, alterations in low density lipoproteins, alterations in glucose level, increase in bleeding time and abdominal pain). Withdrawal rate of participants among the intervention and control groups was also recorded. Other outcomes were recorded, if available: admission rate, use of steroids, disease activity at the end of follow-up period and quality of life. However, most of these data were not available. Studies reporting only surrogate outcomes (e.g. serum or tissue levels of cytokines or inflammatory markers) were excluded.

Search methods for identification of studies

Search methods for identification of studies

Electronic databases

An on-line database literature search from inception to November 2013 was performed for human studies, without language restrictions, using the following databases: MEDLINE (NLM, National Library of Medicine, Bethesda), EMBASE (Elsevier, NY) and HealthSTAR on OVID, as well as PubMed (NLM), the Cochrane Central Register of Controlled Trials (CENTRAL) and ACP journal club. On-going trials were identified from the registry link: www.clinicaltrials.gov. The search strategies used for each database are documented in Appendix 1. All abstracts found by the above search strategy underwent individual screening for eligibility by DT.

Other sources
Additional citations were identified by manually searching the references of articles retrieved from the computerized databases and relevant review articles. Unpublished studies were sought by contacting experts in the field, but none were identified.

Data collection and analysis

Selection of studies
Abstracts of all articles meeting the above search strategy were screened for eligibility. Full text studies were retrieved if they were potentially eligible for inclusion. The retrieved full text articles were then independently reviewed by DT and AMG for eligibility. Disagreements were to be resolved by consensus between the remaining investigators.

Data extraction and management
Two investigators (DT, AMG) independently completed a data extraction form for all eligible studies. The following data were retrieved:

1. General information: title, journal, year, published or unpublished.
2. Study information: design, ways used to ensure adequacy of randomization, concealment of allocation and blinding, power calculation (a priori and post hoc).
3. Intervention: form and dose of n-3, type of comparison group, special diet used.
4. Eligibility: inclusion and exclusion criteria, total number screened and randomized.
5. Baseline characteristics (in each group): age, sex, race, disease severity (and how evaluated), concurrent medications used.
6. Follow-up: length of follow-up, assessment of compliance, withdrawals and loss to follow-up.
7. Outcome: time to first relapse, disease activity at each evaluation time (and how was assessed) number of relapses during the follow-up period, adverse events, use of steroid, number of hospital admissions and weight.

Assessment of methodological quality of included studies

Two authors (RL and OL) independently assessed the quality of included studies using the Cochrane risk of bias tool (Higgins 2011). Factors assessed included:

  • random sequence generation;

  • allocation concealment;

  • blinding;

  • incomplete outcome data;

  • selective outcome reporting; and

  • other potential sources of bias.

We rated each of these factors as ‘low risk’, ‘high risk’ or ‘unclear risk’. Disagreements were resolved by consensus.

We used the GRADE approach to assess the overall quality of evidence for the primary outcome and selected secondary outcomes of interest. Outcomes from pooling of randomized trials start as high quality evidence, but may be downgraded due to: (1) risk of bias, (2) indirectness of evidence, (3) inconsistency (unexplained heterogeneity), (4) imprecision (sparse data), and (5) reporting bias (publication bias). The overall quality of evidence for each outcome was determined after considering each of these elements, and categorized as high quality (i.e. further research is very unlikely to change our confidence in the estimate of effect); moderate quality (i.e. further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate); low quality (i.e. 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); or very low quality (i.e. we are very uncertain about the estimate) (Guyatt 2008; Guyatt 2011; Schünemann 2011).

Missing data
Primary authors were contacted for missing data, but none replied. A sensitivity analysis was planned in this case.

Statistical analysis
Categorical data (as relapsed or not during the follow-up period) for each study were transformed into two by two tables.

Measures of treatment effect
We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes. For the primary analysis the actual relapse rate was used rather than the estimated rate (controlling for censored data), since most studies did not report the estimated relapse rate. The number needed to treat to benefit (NNTB) and the absolute risk reduction (risk difference) and corresponding 95% CI were also calculated where appropriate. For time-to-event data we calculated the hazard ratio (HR) and corresponding 95% CI. No continuous variables (i.e. number of relapses) were reported in the studies.

Meta-analysis
Random-effects or fixed-effect models were used to pool studies depending on clinical and statistical heterogeneity. Weighting was assigned according to the Mantel-Haenszel method. For time-to-event analyses, the generic inverse variance function was used, inputting the lnHR (hazard ratio) with its lnSE (standard error) derived from the reported 95% CI of the HR. The lnSE was obtained using the formula: lnSE=(ln(lower 95% CI limit)-ln(upper 95% CI limit))/3.92.

Assessment of Heterogeneity
First, studies were independently reviewed for any clinical and methodological heterogeneity and possible reasons for heterogeneity were sought. The decision of whether to pool studies was aided by calculating the I2 measure, interpreted as 25% (low heterogeneity), 50% (moderate) and 75% (high) (Higgins 2003). Next, the Cochran Chi2 test for homogeneity (Q test) was calculated, and since the test has low sensitivity to detect heterogeneity, P < 0.1 was considered to be statistically significant.

Subgroup analysis
A priori subgroup analyses were planned, governed by the number of identified studies: different dosing of eicosapentoic acid (EPA), follow-up duration (< 9 months and > 9 months), pediatric versus adult population (< 18 years of age and > 18 years), different formulation of the fish oil (raw, encapsulated, or enteric coated).

Sensitivity analysis
In order to assess the robustness of the eligibility criteria, planned sensitivity analyses included excluding poor quality studies, small studies (< 50 patients) and studies published in abstract form. A funnel plot was constructed to assess the possibility of publication bias.

Results

Description of studies

Results of the search
The initial search yielded 142 non-duplicated articles (See Figure 1). Based on abstract review, all potentially controlled trials and review articles for reference search were retrieved. Nineteen full text articles were assessed for eligibility. Two studies were excluded because they were not randomized controlled trials (Mate 1991; Tsujikawa 2000). Eight studies were excluded because they enrolled only active patients (i.e. focusing on whether n-3 can induce remission (Bamba 2003; Eivindson 2005; Nielsen 2005; Sakurai 2002; Seidman 2003; Socha 2002; Trebble 2004; Trebble 2005). One study was excluded because it enrolled patients with active and inactive Crohn's disease (Lorenz 1989). Two studies were excluded because n-3 treatment was for less than six months (Bjorkkjaer 2004; Geerling 2000). Six studies with a total of 1039 patients were included in this review (table of included studies). Two independent trials (EPIC-1 and EPIC-2) were reported in the same manuscript (Feagan 2008a) and were included in the last update (Turner 2009). No new studies were published since 2008, and thus no additional studies were included in the current review update. Agreement among reviewers regarding the eligibility of the included studies was 100%.

Figure 1.

Study flow diagram.

Included studies:
1. Belluzzi 1996

  • Design: A double blind, placebo-controlled trial of one year duration.

  • Sample size: A total of 78 adults (18 to 67 years of age, 50% men), 39 in each arm.

  • Setting: Outpatient clinics in Italy.

  • Participants: At baseline, participants were in remission (CDAI < 150 for at least 3 months, but less than 2 years) and high risk for relapse, judged by an increase in at least one of three serum inflammatory markers. No concurrent medications were allowed and there were no diet restrictions. Patients were followed every three months until one year.

  • Interventions: Enteric coated fish oil capsule with 60 minutes delay timed release (1.8 g/day of EPA and 0.9 g/day of DHA, as free fatty acids) versus identical placebo of 500 mg Miglyol 812 (a mixed-acid triglyceride of fractionated medium chain fatty acids made up of caprylic and capric acid). The enteric coated time released capsules were used to avoid troubling adverse reactions such as nausea and halitosis thereby improving compliance.

  • Outcomes: Relapse rates over one year of follow-up, as defined by CDAI > 150 or an increase of at least 100 points in CDAI from baseline for two weeks. Adverse events and time to first relapse were also monitored.

2. Lorenz-Meyer 1996

  • Design: A double blind, placebo-controlled trial of one year duration with three groups: n-3, placebo and reduced carbohydrate intake. The data and discussion regarding this study will refer only to the n-3 intervention group in comparison with the placebo group (which was the primary aim of the trial).

  • Sample size: A total of 135 adults (17 to 65 years of age, 31% men), 70 in the n-3 arm and 65 in the placebo arm.

  • Setting: Multicenter study in Germany.

  • Participants: At baseline, participants were in remission (CDAI < 150), induced with a course of corticosteroids. Steroids were still administered during the first two months of the study, but no other co-interventions were allowed. Patients were instructed to consume a diet low in arachidonic acid and rich in fiber and were followed every three months until one year.

  • Interventions: Gelatin n-3 capsules (3.3 g/day of EPA and 1.8 g/day of DHA, as ethyl Esther) versus identical placebo of corn oil. A second intervention group was treated with a low carbohydrate diet but was ignored for the purpose of this review.

  • Outcome: Primary outcome was the relapse free time period after randomization as defined by CDAI > 200 and a change from baseline CDAI by at least 60 points, plus an increase of C-reactive protein serum level two standard deviations above normal mean. Relapse rate and adverse events were also monitored.

3. Belluzzi 1997

  • This study was published in abstract form only. Additional information was supplied by the author by personal communication.

  • Design: A double blind, placebo-controlled trial of one year duration.

  • Sample size: A total of 50 adults (mean age 39 ± 13.8 years in the n-3 group, and 35.2 ± 7.9 in the control group, 58% male), 26 in the n-3 arm and 24 in the control arm.

  • Setting: Outpatients at a single IBD center in Italy.

  • Participants: Crohn's disease patients in remission (CDAI < 150) one month following ileal resection. No co-interventions were administered and no specific diet was prescribed; participants were asked to continue their previous dietary habits.

  • Interventions: The n-3 group received the same regimen as Belluzzi 1996 (enteric coated fish oil capsules with 60 minutes delay time release composed of 1.8 g/day of EPA and 0.9 g/day of DHA, as free fatty acids). Placebo capsules were Miglyol 812, as in Belluzzi 1996.

  • Outcome: Relapse rates during a one year follow-up were recorded. Relapse was measured both clinically (CDAI > 150 with an increase of > 50 points from baseline) and by endoscopic or radiological appearance. For the meta-analysis, only clinical relapse rates were included, similar to the other three included trials.

4. Romano 2005

  • Design: A double blind, placebo-controlled trial of one year duration.

  • Sample size: A total of 38 children (5 to 16 years of age, 53% male), 18 in the n-3 group and 20 in the comparison group.

  • Setting: Pediatric gastroenterology centers in Italy.

  • Participants: At baseline, participants were in remission (PCDAI < 20 for at least two months). Exclusion criteria included previous intestinal resection, previous immunomodulator therapy, and corticosteroid therapy in the last three months. No diet restrictions are reported.

  • Interventions: Time dependent 5-ASA (50 mg/kg/day) plus n-3 in gastro-resistant capsules (TRIOLIP-SOFAR, Italy; 1.2 g/day of EPA and 0.6 g/day of DHA, as triglycerides) versus time dependent 5-ASA (50 mg/kg/day) plus an olive oil placebo.

  • Outcome: Primary outcome was relapse rate within one year follow-up as defined by PCDAI > 20. Time to first relapse was also recorded but not thoroughly presented.

5. Feagan 2008a (EPIC-1)

  • Design: A double blind, placebo-controlled trial of 52 weeks duration.

  • Sample size: A total of 383 adults randomized, but only 363 were eligible for the modified intention-to-treat (ITT) analysis, for which data were included only from patients who received at least 1 dose of the study drug and who provided any post randomization data (mean age 40.5 ± 15.2 years in the n-3 group and 38.2 ± 13.1 in the control group, 45% male), 183 in the n-3 group and 180 in the comparison group. Nine of the excluded patients were enrolled by a single site that violated the protocol in various cases.

  • Setting: Fifty-one IBD sites in Canada, Europe, Israel, and United States between January 2003 and February 2007. Patients were evaluated one week before randomization, at the time of randomization and at 4, 16, 30, 44, and 52 weeks thereafter.

  • Participants: At baseline, eligible participants were in remission (CDAI < 150) for at least three months and had at least one exacerbation within the previous year. Exclusion criteria included allergy or intolerance to n-3 or fish products; treatment with 5-aminosalicylates, immunosuppressives, tumor necrosis factor-α antagonists, or investigational drugs; existence of ostomy or short bowel syndrome; bowel resection or obstruction in the preceding 3 months; malignancy (with the exception of resected basal or squamous cell skin cancer or carcinoma of the cervix in situ); substance abuse; and severe medical diseases other than CD.

  • Interventions: Two time released 1 g gelatin capsules of n-3 twice daily (Epanova; Tillotts Pharma AG, Ziefen, Switzerland) consisted of approximately 2.2 g/day of EPA and 0.8 g/day of DHA as free fatty acids versus identical placebo of four 1 g of medium-chain triglyceride oil. To enhance tolerability, patients began with an initial dose of 1 g/day of the study drug for the first 7 days, increased to 2 g/day for 7 days and then further increased to the final dose. No new medications were allowed after randomization.

  • Outcome: Primary outcome was time to relapse, defined by either an increase of the CDAI score to 150 points or greater and an increase of more than 70 points from the score calculated at the randomization visit, or the initiation of prohibited medical therapy or surgery for symptomatic active CD. Secondary outcomes were the change in mean scores on the CDAI and SF-36, the change in the mean serum triglyceride concentration, and the occurrence of adverse events.

6. Feagan 2008b (EPIC-2)

  • Design: A double blind, placebo-controlled trial of 58 weeks duration.

  • Sample size: A total of 379 adults randomized, but only 375 were eligible and received at least one dose of study medication and thus included in the analysis (mean age 38.5 ± 13.8 years in the n-3 group and 40 ± 13.6 in the control group, 43% male), 187 in the n-3 group and 188 in the comparison group.

  • Setting: Forty-seven IBD sites in Canada, Europe, Israel, and United States between January 2003 and February 2007. Patients were evaluated at 8 weeks before randomization, at the time of randomization and at 2, 8, 16, 30, 44, and 58 weeks thereafter.

  • Participants: Patients with active disease were treated with a standardized 16-week tapering course of either prednisone or budesonide at initial doses of 40 mg once daily and 9 mg once daily, respectively. If the CDAI score was < 150 points 8 weeks after the initiation of corticosteroid, than the patient was eligible for randomization. At this time, patients were receiving either 20 mg/day of prednisone or 6 mg/day of budesonide. Exclusion criteria were similar to those described in EPIC-1.

  • Interventions: Similar to the EPIC-1 trial. Corticosteroids were tapered off over 8 weeks.

  • Outcome: Primary and secondary outcome measures were similar to those used in EPIC-1. In addition, an increase of the corticosteroid dose to control symptoms was considered a failure of treatment.

Risk of bias in included studies

None of the eligible articles were excluded based on poor quality. The results of the risk of bias analysis are summarized in Figure 2. Lorenz-Meyer 1996 did not describe methods used for randomization or allocation concealment and was rated as unclear for these items. Follow-up was adequate; however, the study had a drop-out rate of 8/70 (11%) in the intervention arm and 7/65 (11%) in the control arm. Another 7 and 8 patients, respectively, violated the protocol but the results represent an ITT analysis. Belluzzi 1996 was a well designed study, but the report is lacking description on the methods used for randomization and allocation concealment. Blinding and follow-up were well described. The drop-out rate was 9%: 3% lost to follow-up and 6% withdrew because of diarrhea. These patients were not included in the relapse rate calculation and, thus, we performed sensitivity analysis to account for this potential bias. Belluzzi 1997 was published as an abstract, with additional details supplied directly by the author. The drop-out rate was high (16%), and only 16/26 in the n-3 arm and 15/24 in the control arm were assessed for the primary outcome (endoscopic recurrence). Patients with clinical relapse were excluded from the analysis and this could be a source of attrition bias. Romano 2005 was a small but well designed study. The report lacked a description of the methods used for randomization and allocation concealment. A concern was raised from the unexpectedly high rate of relapse among the control group. Follow-up was adequate and no patient dropped-out. The results of laboratory testing were not reported and this item was rated as high risk of bias.

Figure 2.

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

Feagan 2008a reports the results of the EPIC-1 and EPIC-2 studies. In these well designed, performed and reported studies, eligible patients were randomized in a 1:1 ratio using a central randomization number generator stratified by the induction therapy received prior to randomization or the duration of remission. Neither the investigators nor the patients were aware of the treatment assignment. Adherence to the study drug as assigned was evaluated at each clinic visit by interviewing the patient and by capsule counts. Lost to follow-up (not including patients that terminated the study early due to clinical relapse) was high but still in the acceptable range: 15.1% in EPIC-1 and 12.8% in EPIC-2. One critique of these studies is that the sample size calculation was performed for relapse rate while the primary outcome was based on survival analysis.

Effects of interventions

See: Summary of findings for the main comparison

Relapse rate
All included studies reported the relapse rate at 1 year. Belluzzi 1996 found that significantly less patients from the intervention group relapsed (n = 11, 28%) compared to placebo (n = 27, 69%; P < 0.001) and concluded that enteric coated, timed release n-3 is highly effective in maintaining remission in Crohn's disease. This was not an ITT analysis as the outcome of patients who dropped out due to relocation (n = 2, 3%) or adverse events (n = 5, 6%) was not recorded. However, extrapolating from the survival curve, the estimated 1-year relapse rate was 39% in the intervention arm and 75% in the placebo arm. Lorenz-Meyer 1996 found no difference in the relapse rate of the intervention group (n = 40, 57%) compared to placebo (n = 36, 55%; P = 0.84). Extrapolating from the survival curve, the estimated one year relapse rate was 69% in both groups. The authors concluded that gelatin capsules of ethyl ester fish oil capsules are not effective for maintenance of remission in Crohn's disease. Belluzzi 1997 found no benefit for n-3 therapy for maintenance of remission after ileal resection. During the one year follow-up, less patients from the intervention group experienced clinical relapse (n = 2, 8% versus n = 5, 21%; P = 0.24) or histological relapse compared to placebo (n = 9, 34% versus n = 15, 62%; P = 0.09). The authors concluded that enteric coated, timed release fish oil seems to be effective for maintenance of remission after ileal resection in Crohn's disease. A very high relapse rate was found in the placebo group of the Romano 2005 study (n = 19/20, 95% in the placebo group compared with n = 11/18, 61% in the intervention group; P < 0.001). Romano 2005 concluded that enteric coated n-3 in addition to 5-ASA are effective for maintenance of remission in pediatric Crohn's disease. In this study compliance was optimal, no patients were lost to follow-up and all patients were analyzed.

In both EPIC-1 and EPIC-2 trials (Feagan 2008a), the largest of all existing studies, no significant difference in the relapse rate was found between the patients treated with n-3 or placebo. In EPIC-1, 54/183 (29.5%) treated with n-3 relapsed compared to 62/180 (34.4%) in the placebo group (P = 0.31). To control for 55 patients who discontinued the intervention prematurely but did not experience a relapse (26 in the n-3 group and 29 in the placebo group) a survival analysis was used, estimating the 1-year relapse rate of the n-3 group to be 31.6%, compared with 35.7% of the placebo group (P = 0.30). In EPIC-2, the relapse rate was 84/187 (44.9%) and 94/188 (50%) in the n-3 and placebo groups, respectively (P=0.38). The 1-year relapse rate controlled for 48 patients who discontinued the intervention prematurely but did not experience a relapse (30 in the n-3 group and 18 in the placebo group) was estimated at 47.8% and 48.8% in the n-3 and placebo groups, respectively (P = 0.48).

Since all studies shared the primary outcome (relapse rate over 1 year in quiescent CD patients) the data were pooled in a meta-analysis (See Analysis 1.1). In the case of Belluzzi 1997, clinical relapse was included (in contrast with endoscopic or radiographic relapse) to make it comparable with the other studies. The pooled risk ratio was statistically significant in favor of omega-3 fatty acids. Thirty-nine per cent of patients in the n-3 group relapsed at 12 months compared to 47% of placebo patients (6 studies, 1039 patients; RR 0.77, 95% CI 0.61 to 0.98). A GRADE analyses rated the overall quality of the evidence for the primary outcome (i.e. relapse) as very low due to unexplained heterogeneity (I2 = 58%), potential publication bias, and a high or unknown risk of bias in four studies in the pooled analysis. Although each study is somewhat different (i.e. one pediatric, one looked at post resection maintenance, one published in an abstract form, and some used a different placebo), the study by Lorenz-Meyer 1996 differed the most having used a different formulation and dose of n-3. Thus, a subgroup analysis of the five studies that used enteric coated capsules was performed (See Analysis 1.2). There was a reduction in the risk of relapse with the use of enteric coated n-3 compared with placebo with statistically significant heterogeneity (P = 0.05, I2 = 58%). The pooled effect was statistically significant (RR 0.71, 95% CI 0.54 to 0.93). This analysis was repeated after considering all drop-out patients in the intervention arm of Belluzzi 1996 as failures and all drop-outs in the control arm as successes (See Analysis 1.3), but this did not alter the results (RR 0.77, 95% CI 0.64 to 0.93). As shown in Analysis 1.4, the absolute risk reduction was 17% (95% CI 4% to 30%), and the calculated NNTB to prevent one relapse over a one year period was 5 (95% CI 3 to 25).

A sensitivity analysis excluding the abstract publication (See Analysis 1.5) did not change the results (RR 0.72; 95% CI 0.54 to 0.96). When the pediatric study by Romano 2005 was excluded (See Analysis 1.6) the risk ratio was no longer statistically significant (RR 0.71; 95% CI 0.50 to 1.01). When including the estimated one year relapse rate (Belluzzi 1996; Feagan 2008a; Lorenz-Meyer 1996), rather than the actual relapse rate, the pooled risk ratio was no longer statistically significant (Analysis 1.7; RR 0.61, 95% CI 0.37 to 1.02; I2 = 56%). When combining only the two largest and most rigorously performed studies, EPIC-1 and EPIC-2, the risk ratio was not statistically significant (See Analysis 1.8). Thirty-seven per cent of patients in the n-3 group relapsed at 12 months compared to 42% of placebo patients (2 studies, 738 patients; RR 0.88, 95%CI 0.74 to 1.05). No heterogeneity was detected for this comparison (I2 = 0%). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (294 events).

The small number of included studies limited the ability to construct a valid funnel plot. Nonetheless, the funnel plot (Figure 3) suggests the possibility of publication bias, with the representation of three positive but no negative low weighted studies.

Time to first relapse
Five studies reported on time to first relapse. Romano 2005 reported the median time to first relapse which was eight months in the intervention group compared to one month in the placebo group. No survival analysis or formal comparisons were presented. Belluzzi 1996 presented a survival curve; the median relapse free time was four months in the placebo group compared to greater than one year in the fish oil group (log rank test 0.006). At the end of the follow-up period, 23 of the 39 patients in the intervention arm (59%) and 10 of the 39 patients in the placebo group (26%) were still in remission (P = 0.003). In EPIC-1, EPIC-2 (Feagan 2008a) and Lorenz-Meyer 1996 a survival analysis was the primary aim. In Lorenz-Meyer 1996, extrapolating from the Kaplan Meier curve, the median relapse free periods of the placebo and the intervention arms were 133 and 159 days, respectively. This difference was not significant in both the ITT and per protocol analyses. Similarly, the proportion of relapse free patients after one year of follow-up was 31% in both groups.

Figure 3.

Only EPIC-1 and EPIC-2 reported the Hazard Ratio (HR) with 95% CI (HR 0.82, 95% CI 0.57 to 1.18 for EPIC-1, and HR 0.90, 95% CI 0.67 to 1.21 for EPIC-2). The pooled log HR did not show any superiority for n-3 treatment relative to placebo (Analysis 1.9; HR 0.87, 95% CI 0.69 to 1.09). No heterogeneity was detected for this comparison (I2 = 0%).

Disease activity at the end of the year
Belluzzi 1996 reported on change of disease activity at the end of the follow-up period. The reduction in three inflammatory markers (erythrocytes sedimentation rate, serum alpha 2 globulins and alpha 1-acid glycoprotein) was significantly larger in the fish oil group compared to placebo. The EPIC-1 and EPIC-2 studies reported no significant differences between the study groups in CDAI scores, but data were not shown (Feagan 2008a).

Biological effect of n-3
Five studies reported the biological effect of treatment. Two studies evaluated the incorporation of n-3 into red blood cells (RBC) membranes and three studies evaluated the change in serum triglycerides. Belluzzi 1996 presented data on patients who remained in remission at the end of the follow-up period. Omega 3 fatty acids replaced 50% of the RBC arachidonic acid in the intervention arm and remained unchanged in the placebo arm. Romano 2005 showed that all subjects in the intervention arm had a statistically significant increase in the RBC concentration of EPA and DHA, and a decrease in arachidonic acid. Lorenz-Meyer 1996, and Feagan 2008a (EPIC-1 and EPIC-2) reported a significant decrease in serum triglycerides among n-3 treated patients compared to placebo.

Quality of life
No significant difference in SF-36 scores was found between the study groups in the EPIC-1 and EPIC-2 studies (Feagan 2008a). These data were not shown.

Adverse events
Overall, no serious adverse events were reported in any of the trials. Belluzzi 1997 did not report on adverse events, but reported by personal communication that no serious adverse events occurred in either arm. Adverse events that were different between the treatment arms in at least one of the remaining five studies are summarized in Additional Table 1. Romano 2005 reported that there were no adverse events in either group, but no explicit list of items are presented. Belluzzi 1996 reported that 4/39 patients in the intervention arm withdrew due to adverse events compared to 1/39 patients in the placebo arm (due to diarrhea). Discontinuation rates secondary to adverse events in EPIC-1 and EPIC-2 (Feagan 2008a) were 9/183 versus 7/180 and 9/187 versus 5/188 in the n-3 and the placebo groups, respectively. In EPIC-1, 79.2% of patients who received n-3 had adhered to the study drug, compared with 75.6% of those who received placebo (P=0.40). The corresponding adherence rates for EPIC-2 were 75.4% and 81.4%, respectively (P=0.16).

Table 1. Adverse events that were different between the intervention and control arms
StudyBelluzzi 1996Lorenz-Meyer 1996Romano 2005Feagan 2008; EPIC 1Feagan 2008; EPIC 2
Diarrhea -intervention vs control4/39 (10%) vs. 1/39 (3%)1/70 (1%) vs. 1/65 (2%)0/18 (0%) vs. 0/20 (0%)35/187 (19%) vs. 21/184 (11%)44/189 (23%) vs 37/188 (20%)
Halitosis, or heartburn -intervention vs control0/39 (0%) vs. 0/39 (0%)10/70 (14%) vs. 2/65 (3%)0/18 (0%) vs. 0/20 (0%)not reported but dysgeusia: 2/187 (1%) vs 1/184 (0.5%)not reported but dysgeusia: 10/189 (5%) vs. 2/188 (1%)
Nausea -intervention vs control0/39 (0%) vs. 0/39 (0%)0/70 (0%) vs. 0/65 (0%)0/18 (0%) vs. 0/20 (0%)17/187 (9%) vs. 4/184 (2%)30/189 (16%) vs. 19/188 (10%)
All upper GI symptoms -intervention vs. controls (halitosis, nausea, vomiting, dyspepsia, dysgeusia and bloating)0/39 (0%) vs. 0/39 (0%)10/70 (14%) vs. 2/65 (3%)0/18 (0%) vs. 0/20 (0%)27/187 (14%) vs..12/184 (6.5%)67/189 (35.5%) vs. 45/188 (24%)

Lorenz-Meyer 1996 was excluded from the meta-analysis of adverse events because the pathophysiology of the adverse events in that study was very different than the others (upper gastrointestinal symptoms with regular gelatin capsules compared to more lower gastrointestinal symptoms with the timed release capsules used in all the other studies). In the pooled analyses, there was significantly more diarrhea and upper gastrointestinal symptoms with n-3 treatment compared to placebo. Nineteen per cent of n-3 patients had diarrhea compared to 14% of placebo patients (Analysis 1.10, 4 studies, 862 patients; RR 1.36, 95% CI 1.01 to 1.84). Twenty-one per cent of n-3 patients had upper gastrointestinal symptoms compared to 12% of the placebo group (Analysis 1.11, 5 studies, 999 patients; RR 1.65, 95% CI 1.25 to 2.18). No heterogeneity was detected for these comparisons (I2 = 0% for both comparisons).

Other outcomes
Other planned outcomes (i.e. steroid use, admission rate, and number of exacerbations) were not reported in any of the studies.

Discussion

Despite the fact that the EPIC studies did not show a clinical benefit to n-3, the pooled effect of the six included studies was marginally significant (RR 0.77, 95% CI 0.61 to 0.98). However, this presumed benefit is probably misleading for several reasons:

1) There was a large degree of heterogeneity in the pooled analysis that could not be explained on the basis of different methodology of the studies;
2) The statistically significant benefit did not hold when including the estimated, rather than the actual,one year relapse rate (calculated using survival estimates to account for censored data), nor did it hold when the small pediatric study (Romano 2005) was excluded; and
3) A funnel plot suggested publication bias, wherein small negative trials were under-represented.

Taken together, it is likely that the rigorously performed EPIC studies produced more precise estimates of the true treatment effect than the pooled analysis. It is important to emphasize that the sample size of each EPIC study was approximately double the sample size of all other included studies combined.

This conclusion is disappointing in view of indirect evidence that supports the effectiveness of n-3 in modulating inflammation of IBD. Orally administered n-3 is readily incorporated in IBD affected bowel mucosa (Hillier 1991), thereby reducing the production of local proinflammatory cytokines (Hillier 1991; Meister 2005). Fish oil also alters signaling pathways and has a direct effect on the expression of many genes (Bassaganya-Riera 2006; Deckelbaum 2006; Roy 2007). Fish oil proved to be protective in animal models with experimental IBD (Nieto 2002; Socha 2005; Vilaseca 1990). In a recent study, n-3 did not protect pigs from dextran sodium sulfate (DSS) induced IBD, but accelerated clinical remission (Bassaganya-Riera 2006). Finally, some reports indicated depleted serum n-3 in IBD patients (Kuroki 1997; Siguel 1996), but this was not replicated by others (Figler 2007; Socha 2005). An initial uncontrolled human study of fish oil supplementation, showed promising results for maintenance of remission in CD (Mate 1991).

It is difficult to explain the limited or absent clinical benefit of n-3 in Crohn's disease in view of the strong biologic rationale and the extensive supportive evidence from tissue samples and animal models. One explanation may lie in the delivery system of the drug. However, the n-3 fatty acids were being consumed and absorbed in all studies, as reflected by decreased serum triglycerides and altered fatty acid composition of RBC. The dose might have been inadequate or the formulation not optimal. In a scientific study aimed to find the optimal chemical formulation in IBD, n-3 as enteric coated fatty acids with 60 minutes timed release had the highest serum and RBC incorporation rate and the lowest rate of adverse events, in comparison to different timed release and triglyceride compounds (Belluzzi 1994). The chemical formulation, thus, also seems to be important. It had been shown that the intestinal absorption of n-3 is higher with free fatty acids (e.g. EpanovaTM) compared with triacylglycerol (e.g. Max-EPA) or ester formulations (el Boustani 1987; Lawson 1988), probably due to enhanced absorption. Accordingly, the smaller effect size found in Romano 2005 could be attributed to the ethyl ester formulation that was used compared to the free fatty acids used in the other studies. In contrast, the EPIC studies failed to show benefit with EpanovaTM tablets that contain timed release free fatty acids (albeit in a soft gelatin capsules; the authors claim that its bioavailability is similar to the hard capsules used by Belluzzi 1996). Notwithstanding the abovementioned data, it does appear that the biological effect of n-3 is more complex than once believed, and likely includes both anti-inflammatory and pro-inflammatory actions (Hokari 2013). This is also supported by a few animal studies that actually demonstrated a worsening of experimental colitis in mice receiving n-3 supplementation (Matsunaga 2008; Woodworth 2010). It has also been suggested that the administration of n-3 to established patients, as in the human interventional studies reviewed here, is fundamentally different from the animal studies in which n-3 was generally administered before the onset of disease (Marion-Letellier 2013).

Fish oil is considered very safe, but in the pooled analyses troublesome adverse events such as diarrhea and upper gastrointestinal symptoms were more frequent than in controls. Findings that n-3 may alter LDL level, bleeding time and glucose level have not been consistently reproduced (Oh 2005), and did not come up in any of the included studies. The non-serious but bothersome adverse events include unpleasant taste, halitosis, heartburn, nausea and diarrhea (Kim 1996; Lorenz 1989). It has been shown, that unlike raw fish, various over-the-counter n-3 preparations have at the most negligible amounts of mercury and organochlorines (Melanson 2005). Another concern relates to infants whose growth rate may be altered with high intake ratios of EPA to DHA (Akabas 2006).

A limitation of this review is the clinical heterogeneity among the included studies. The studies used different preparations of omega-3 fatty acids, with different compositions and different delivery systems. The placebo also varied among the trials, and it is possible that these placebos were not inert, with potentially either positive or negative effects. One of the studies was in the post-operative setting and another examined only pediatric patients. On the other hand, the studies were very similar in other aspects: all included only CD patients in remission, and used a similar end point of relapse rate over an identical follow-up period of one year. The use of any drug during a quiescent period is a tradeoff between the efficacy for maintaining remission and the associated adverse events. The current effective maintenance therapies for Crohn's disease, immunomodulators and infliximab, possess potentially concerning adverse reactions. Besides serious short term adverse events (e.g. infections, infusion reactions, pancreatitis, hepatitis and severe cytopenia), it has been shown that 6-mercaptopurine and azathioprine (Kandiel 2005), and recently also infliximab (Thayu 2005), may increase the risk of developing lymphoma. The search for an effective yet safe drug to maintain remission in Crohn's disease continues.

Authors' conclusions

Implications for practice

Evidence from two large high quality studies suggests that omega 3 fatty acids are probably ineffective for maintenance of remission in CD. Omega 3 fatty acids appear to be safe although they may cause diarrhea and upper gastrointestinal tract symptoms.

Implications for research

Further adequate sample-sized clinical trials are needed utilizing effective delivery methods of omega 3 fatty acids. Future studies should use different formulations of n-3 in the intervention arm, inert placebo oil, and include long-term outcome data. However, before more large scale RCTs evaluating omega 3 products are conducted further basic research regarding the putative mechanism of action and the role of local drug delivery is needed.

Acknowledgements

Funding for the IBD/FBD Review Group (September 1, 2010 - August 31, 2015) has been provided by the Canadian Institutes of Health Research (CIHR) Knowledge Translation Branch (CON - 105529) and the CIHR Institutes of Nutrition, Metabolism and Diabetes (INMD); and Infection and Immunity (III) and the Ontario Ministry of Health and Long Term Care (HLTC3968FL-2010-2235).

Miss Ila Stewart has provided support for the IBD/FBD Review Group through the Olive Stewart Fund.

The authors would like to thank Professor Andrea Belluzzi for providing additional information on his study.

Data and analyses

Download statistical data

Comparison 1. Omega-3 versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Relapse rate at one year (all studies)61039Risk Ratio (M-H, Random, 95% CI)0.77 [0.61, 0.98]
2 Relapse rate at one year (enteric coated studies)5904Risk Ratio (M-H, Random, 95% CI)0.71 [0.54, 0.93]
3 Relapse rate at one year (sensitivity analysis of Belluzi 1996)5904Risk Ratio (M-H, Random, 95% CI)0.77 [0.64, 0.93]
4 Relapse rate at one year (enteric coated - risk difference)5904Risk Difference (M-H, Random, 95% CI)-0.17 [-0.30, -0.04]
5 Relapse rate at one year (sensitivity analysis - excluding abstract study)4854Risk Ratio (M-H, Random, 95% CI)0.72 [0.54, 0.96]
6 Relapse rate at one year (sensitivity analysis - excluding pediatric study)4866Risk Ratio (M-H, Random, 95% CI)0.71 [0.50, 1.01]
7 Relapse rate at one year (all studies, rate in EPIC studies by survival estimates)61039Risk Ratio (M-H, Random, 95% CI)0.81 [0.66, 1.00]
8 Relapse rate at one year (only EPIC studies)2738Risk Ratio (M-H, Random, 95% CI)0.88 [0.74, 1.05]
9 Relapse at one year, survival analysis (Hazard Ratios of the EPIC studies)2 hazard ratio (Random, 95% CI)0.87 [0.69, 1.09]
10 Adverse events rate: Diarrhea4862Risk Ratio (M-H, Random, 95% CI)1.36 [1.01, 1.84]
11 Adverse events rate: Upper GI symptoms (nausea, vomiting, halitosis, heartburn, dyspepsia, disgeusia and bloating)5999Risk Ratio (M-H, Random, 95% CI)1.65 [1.25, 2.18]
Analysis 1.1.

Comparison 1 Omega-3 versus placebo, Outcome 1 Relapse rate at one year (all studies).

Analysis 1.2.

Comparison 1 Omega-3 versus placebo, Outcome 2 Relapse rate at one year (enteric coated studies).

Analysis 1.3.

Comparison 1 Omega-3 versus placebo, Outcome 3 Relapse rate at one year (sensitivity analysis of Belluzi 1996).

Analysis 1.4.

Comparison 1 Omega-3 versus placebo, Outcome 4 Relapse rate at one year (enteric coated - risk difference).

Analysis 1.5.

Comparison 1 Omega-3 versus placebo, Outcome 5 Relapse rate at one year (sensitivity analysis - excluding abstract study).

Analysis 1.6.

Comparison 1 Omega-3 versus placebo, Outcome 6 Relapse rate at one year (sensitivity analysis - excluding pediatric study).

Analysis 1.7.

Comparison 1 Omega-3 versus placebo, Outcome 7 Relapse rate at one year (all studies, rate in EPIC studies by survival estimates).

Analysis 1.8.

Comparison 1 Omega-3 versus placebo, Outcome 8 Relapse rate at one year (only EPIC studies).

Analysis 1.9.

Comparison 1 Omega-3 versus placebo, Outcome 9 Relapse at one year, survival analysis (Hazard Ratios of the EPIC studies).

Analysis 1.10.

Comparison 1 Omega-3 versus placebo, Outcome 10 Adverse events rate: Diarrhea.

Analysis 1.11.

Comparison 1 Omega-3 versus placebo, Outcome 11 Adverse events rate: Upper GI symptoms (nausea, vomiting, halitosis, heartburn, dyspepsia, disgeusia and bloating).

Appendices

Appendix 1. Electronic Search Strategies

Appendix I – Electronic Search Strategies

Database Search Query Results
    

PUBMED

run Nov. 22, 2013

1(singl* OR doubl* OR tripl* OR trebl* OR blind* OR mask* OR placebo* OR single-blind* OR double-blind* OR triple-blind* OR random* OR (controlled clinical))2,478,073
2(crohn* OR enteritis OR ileitis)53,319
3(#1 AND #2)6,478
4((fish oil) OR efamed OR (fish oils) OR promega OR (super epa) OR superepa OR (tuna oil) OR (tuna oils))22,213
5(omega-3 OR (omega 3) OR (n-3 fatty acid) OR (n3 fatty acid) OR (n-3 PUFA) OR (n3 PUFA) OR (n-3 polyunsaturated) OR (n3 polyunsaturated) OR (n3 poly unsaturated) OR (n-3 poly unsaturated) OR (seal oil) OR (krill oil))21,926
6(icosapentaenoic OR docosahexaenoic OR linolenic OR eicosapentaenoic OR alpha-linolenic OR EPA OR DHA)30,125
7(#4 OR #5 OR #6)45,886
8(#3 AND #7)57
    
EMBASE + EMBASE Classic (1947 – 2013) run Nov. 22, 20131random$.tw.882,607
2factorial$.tw.22,991
3(crossover$ or cross over$ or cross-over$).tw.72,085
4placebo$.tw.207,389
5single blind.mp.24,794
6double blind.mp.186,064
7triple blind.mp.338
8(singl$ adj blind$).tw.14,471
9(double$ adj blind$).tw.151,927
10(tripl$ adj blind$).tw.383
11assign$.tw.242,174
12allocat$.tw.83,271
13crossover procedure/39,339
14double blind procedure/123,454
15single blind procedure/18,566
16triple blind procedure/60
17randomized controlled trial/362,954
18or/1-171,298,268
19(exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.)5,891,223
2018 not 191,115,668
21exp Crohn disease/ or crohn*.mp. or exp colon Crohn disease/66,863
22(enteritis or ileitis).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]63,073
2321 or 22108,448
2420 and 234,950
25fish oil.mp. or exp fish oil/14,247
26(efamed or fish oils or promega or "super epa" or superepa or "tuna oil" or "tuna oils").mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]3,778
27omega-3.mp. or exp omega 3 fatty acid/21,010
28("omega 3" or "n-3 fatty acid" or "n3 fatty acid" or "n-3 PUFA" or "n3 PUFA" or "n-3 polyunsaturated" or "n3 polyunsaturated" or "n3 poly unsaturated" or "n-3 poly unsaturated" or "seal oil" or "krill oil").mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]23,487
 29icosapentaenoic acid.mp. or exp icosapentaenoic acid/10,769
30docosahexaenoic acid.mp. or exp docosahexaenoic acid/14,509
31linolenic acid.mp. or exp linolenic acid/11,370
32("eicosapentaenoic acid" or "eicosapentaenoic acid*" or "icosapentaenoic acid*" or "docohexaenoic acid*" or "alpha-linolenic acid" or "linolenic acid*" or "alpha-linolenic acid*" or EPA or DHA).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]36,564
3325 or 26 or 27 or 28 or 29 or 30 or 31 or 3260,990
3424 and 3394
    

All OVID Medline (1946 – present)

run Nov. 22, 2013

1random$.tw.73,9513
2factorial$.tw.18,494
3(crossover$ or cross over$ or cross-over$).tw.64,433
4placebo$.tw.169,408
5single blind.mp.24,116
6double blind.mp.160,664
7triple blind.mp.260
8(singl$ adj blind$).tw.11,808
9(double$ adj blind$).tw.121,299
10(tripl$ adj blind$).tw.320
11assign$.tw.213,631
12allocat$.tw.71,382
13crossover procedure/0
14double blind procedure/0
15single blind procedure/0
16triple blind procedure/0
17randomized controlled trial/390,954
18or/1-171,106,670
19(exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.)4,056,651
2018 not 19981,666
21exp Crohn disease/ or crohn*.mp. or exp colon Crohn disease/41,252
22(enteritis or ileitis).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]16,138
2321 or 2254,204
2420 and 232,323
25fish oil.mp. or exp fish oil/20,955
26(efamed or fish oils or promega or "super epa" or superepa or "tuna oil" or "tuna oils").mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]6,963
27omega-3.mp. or exp omega 3 fatty acid/19,961
28("omega 3" or "n-3 fatty acid" or "n3 fatty acid" or "n-3 PUFA" or "n3 PUFA" or "n-3 polyunsaturated" or "n3 polyunsaturated" or "n3 poly unsaturated" or "n-3 poly unsaturated" or "seal oil" or "krill oil").mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]15,620
29icosapentaenoic acid.mp. or exp icosapentaenoic acid/30
30docosahexaenoic acid.mp. or exp docosahexaenoic acid/7,754
31linolenic acid.mp. or exp linolenic acid/6,995
32("eicosapentaenoic acid" or "eicosapentaenoic acid*" or "icosapentaenoic acid*" or "docohexaenoic acid*" or "alpha-linolenic acid" or "linolenic acid*" or "alpha-linolenic acid*" or EPA or DHA).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]25,252
3325 or 26 or 27 or 28 or 29 or 30 or 31 or 3240,767
3424 and 3338
    

OVID HealthSTAR (1966 – Oct. 2013)

run Nov. 22, 2013

1random$.tw.506,378
2factorial$.tw.9,199
3(crossover$ or cross over$ or cross-over$).tw.46,972
4placebo$.tw.137,186
5single blind.mp.23,308
6double blind.mp.160,326
7triple blind.mp.199
8(singl$ adj blind$).tw.9,666
9(double$ adj blind$).tw.110,768
10(tripl$ adj blind$).tw.246
11assign$.tw.108,502
12allocat$.tw.46,302
13crossover procedure/0
14double blind procedure/0
15single blind procedure/0
16triple blind procedure/0
17randomized controlled trial/174,967
18or/1-17742,216
19(exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.)84,390
2018 not 19741,219
21exp Crohn disease/ or crohn*.mp. or exp colon Crohn disease/19,397
22(enteritis or ileitis).mp. [mp=title, original title, abstract, name of substance word, subject heading word]4,406
2321 or 2223,010
2420 and 231,651
25fish oil.mp. or exp fish oil/8,731
26(efamed or fish oils or promega or "super epa" or superepa or "tuna oil" or "tuna oils").mp. [mp=title, original title, abstract, name of substance word, subject heading word]2,663
27omega-3.mp. or exp omega 3 fatty acid/8,565
28("omega 3" or "n-3 fatty acid" or "n3 fatty acid" or "n-3 PUFA" or "n3 PUFA" or "n-3 polyunsaturated" or "n3 polyunsaturated" or "n3 poly unsaturated" or "n-3 poly unsaturated" or "seal oil" or "krill oil").mp. [mp=title, original title, abstract, name of substance word, subject heading word]7,187
29icosapentaenoic acid.mp. or exp icosapentaenoic acid/6
30docosahexaenoic acid.mp. or exp docosahexaenoic acid/2,341
31linolenic acid.mp. or exp linolenic acid/1,890
32("eicosapentaenoic acid" or "eicosapentaenoic acid*" or "icosapentaenoic acid*" or "docohexaenoic acid*" or "alpha-linolenic acid" or "linolenic acid*" or "alpha-linolenic acid*" or EPA or DHA).mp. [mp=title, original title, abstract, name of substance word, subject heading word]9,522
3325 or 26 or 27 or 28 or 29 or 30 or 31 or 3216,205
3424 and 3328
    
Cochrane Library (CENTRAL) run Nov. 22, 20131crohn* or enteritis or ileitis1,797
2(fish oil) or efamed or (fish oils) or promega or (super epa) or superepa or (tuna oil) or (tuna oils)1,535
3

omega-3 or (omega 3) or (n-3 fatty acid) or (n3 fatty acid) or (n-3 PUFA) or (n3 PUFA) or (n-3 polyunsaturated) or (n3 polyunsaturated) or (n3 poly

unsaturated) or (n-3 poly unsaturated) or (seal oil) or (krill oil)

2,930
4

icosapentaenoic or docosahexaenoic or linolenic or eicosapentaenoic or

alpha-linolenic or EPA or DHA

2,168
5#2 or #3 or #44,549
6#1 and #549*
    

ACP Journal Club

run Nov. 22, 2013

 “crohn*” OR “ileitis” OR “enteritis”7 hits, none of which were related to fish oils
    
DDW abstracts (1981-2010; later abstracts are found in EMBASE) (crohn* OR ileitis OR enteritis) AND (omega OR fish OR tuna OR seal OR krill OR polyunsaturated OR icosapentaenoic OR docosahexaenoic OR linolenic OR eicosapentaenoic OR PUFA OR DHA OR EPA OR fatty OR promega OR efamed)24

* Of those 49 hits, only 27 were references to clinical trials and thus only those 27 hits were exported to Endnote.

What's new

DateEventDescription
18 June 2014AmendedContains new information provided by author of included study

History

Protocol first published: Issue 1, 2007
Review first published: Issue 2, 2007

DateEventDescription
30 May 2014AmendedCorrection regarding correspondence with author of included study
22 November 2013New search has been performedNew search, no new studies identified
22 November 2013New citation required but conclusions have not changedUpdated review with two new authors

Contributions of authors

RL Responsible for search for new literature published since the previous review, reviewed and edited the updated manuscript.

OL Participated in review and editing of the updated manuscript.

AMG Formulated the research question, provided IBD expert opinion, selected and reviewed the eligible studies, involved in the analyses, and reviewed the manuscript.

DT Responsible for the literature search, selecting and reviewing the eligible studies, performing the analyses; wrote the previous versions of the manuscript and reviewed the current manuscript.

Declarations of interest

None known.

Sources of support

Internal sources

  • Mount Sinai Hospital, University of Toronto, Toronto, Canada.

  • Department of Health Policy, Management and Evaluation, U of T, Canada.

  • Hospital for Sick Children, Toronto, Canada.

External sources

  • No sources of support supplied

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Belluzzi 1996

MethodsDouble blind, placebo-controlled trial
Participants

N = 39 in each arm

All patients had CDAI < 150 at baseline with an increase in inflammatory markers

InterventionsEnteric coated, n-3 as timed release fatty acids (1.8 g/day of EPA, 0.9 g/day of DHA) versus identical placebo of 500 mg Miglyol 812
Outcomes

Relapse rates over 1 year

Adverse events
Time to first relapse

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Balanced block randomization scheme

The method of randomization was not described

Allocation concealment (selection bias)Unclear riskThe method of allocation concealment was not described
Blinding (performance bias and detection bias)
All outcomes
Low risk

The study medications were packed identically and labelled with each patient’s code number

There was no difference in odor between the fish-oil and placebo preparations, provided the capsules were not broken

Incomplete outcome data (attrition bias)
All outcomes
High riskParticipants who withdrew due to diarrrhea were not included in the relapse rate calculation and it is unclear whether they were included in lab results at the end of the study
Selective reporting (reporting bias)Low riskAll expected outcomes were reported
Other biasLow riskThe study appears to be free of other sources of bias

Belluzzi 1997

MethodsDouble blind, placebo- controlled trial
Participants

N = 26 in the intervention arm and 24 in the control arm

Patients in remission one month following ileal resection

InterventionsEnteric coated, n-3 as timed release fatty acids (1.8 g/day of EPA, 0.9 g/day of DHA) versus identical placebo of 500 mg Miglyol 812
OutcomesClinical and endoscopic relapse rates over 1 year
NotesPublished in abstract form
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

The random list was prepared by the pharmacist of the company producing the product using a balanced block randomization scheme

The method of randomization was not described

Allocation concealment (selection bias)Low riskCentrallized pharmacy randomization
Blinding (performance bias and detection bias)
All outcomes
Low riskThe study medications were packed identically and labelled with each patient’s code number
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOnly 16/26 in the n-3 arm and 15/24 in the control arm were assessed for the primary outcome (endoscopic recurrence) This might be due to exclusion of patients with clinical relapse but no explanation was given
Selective reporting (reporting bias)Low riskExpected outcomes were reported
Other biasLow riskThe study appears to be free of other sources of bias

Feagan 2008a

MethodsDouble blind, placebo-controlled trial (EPIC-1)
Participants

n = 183 in the intervention arm and 180 in the control arm

CDAI < 150 for at least three months and at least one exacerbation within the previous year

Interventions

Enteric coated, n-3 as timed release fatty acids (2.2 g/day of EPA, 0.8 g/day of DHA) versus identical placebo of 4 g/day medium-chain triglyceride oil

No new medications were allowed after randomization

Outcomes

Time to relapse

1 year relapse rate

Adverse events

Change in CDAI

Change in SF-36

NotesBoth EPIC-1 and EPIC-2 were reported in one manuscript of Feagan 2008
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskEligible patients were randomly assigned, in a 1:1 ratio using a random number generator
Allocation concealment (selection bias)Low riskBoth studies used a central randomization procedure
Blinding (performance bias and detection bias)
All outcomes
Low risk

Identical placebo

Neither the investigators nor the patients were aware of the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs balanced across intervention groups with similar reasons for withdrawal
Selective reporting (reporting bias)Low riskAll expected outcomes were reported
Other biasLow riskThe study appears to be free of other sources of bias

Feagan 2008b

MethodsDouble blind, placebo- controlled trial (EPIC-2)
Participants

n = 187 in the intervention arm and 188 in the control arm

Steroid induced remission with CDAI < 150 after 8 weeks of treatment

InterventionsSimilar to the EPIC-1 trial; corticosteroids were tapered off over 8 weeks from randomization
OutcomesSame as for EPIC-1 above
NotesBoth EPIC-1 and EPIC-2 were reported in one manuscript (Feagan 2008)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskEligible patients were randomly assigned, in a 1:1 ratio using a random number generator
Allocation concealment (selection bias)Low riskBoth studies used a central randomization procedure
Blinding (performance bias and detection bias)
All outcomes
Low risk

Identical placebo

Neither the investigators nor the patients were aware of the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs balanced across intervention groups with similar reasons for withdrawal
Selective reporting (reporting bias)Low riskAll expected outcomes were reported
Other biasLow riskThe study appears to be free of other sources of bias

Lorenz-Meyer 1996

MethodsDouble blind, placebo-controlled trial
Participants

N = 70 in the intervention arm and 65 in the control arm

CDAI < 150 at baseline

Patients on a diet low in arachidonic acid and rich in fiber

InterventionsNon-enteric coated, n-3 as ethylesther (3.3 g/day of EPA and 1.8 g/day of DHA) versus identical placebo of corn oil
Outcomes

Relapse rates over 1 year

Adverse events

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical placebo of corn oil
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe study had a high drop-out rate, but the drop-out appeared to be balanced: 8/70 (11%) in the intervention arm and 7/65 (11%) in the control arm
Selective reporting (reporting bias)Low riskAll expected outcomes were reported
Other biasLow riskThe study appears to be free of other sources of bias

Romano 2005

  1. a

    Abbreviations: CDAI = Crohn's disease activity index; PCDAI = pediatric Crohn's disease activity index; 5-ASA = 5-amino salicylic acid; EPA = eicosapentanoic acid; DHA = docosahexanoic acid

MethodsDouble blind, placebo-controlled trial
Participants

N = 18 in the intervention arm and 20 in the control arm

PCDAI < 20 at baseline

Interventions

Enteric coated n-3 as triglycerides (1.2 g/day of EPA and 0.6 g/day of DHA) versus placebo of olive oil

Both groups received 5-ASA (50 mg/kg/day)

Outcomes

Relapse rates over 1 year

Time to first relapse

NotesPediatric study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-out rate not specifically reported, but there appear to have been no drop-outs
Selective reporting (reporting bias)High riskLaboratory testing was performed as specified in the methods section, but no results are reported
Other biasLow riskThe study appears to be free of other sources of bias

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Bamba 2003Study enrolled patients with active Crohn's disease
Bjorkkjaer 2004N-3 treatment was for less than 6 months
Eivindson 2005Study enrolled patients with active Crohn's disease
Geerling 2000N-3 treatment was for less than 6 months
Lorenz 1989

Study enrolled both patients with active and non-active Crohn's disease

Attempts to obtain data from the authors on the inactive patients only were unsuccessful

Mate 1991Non-randomized study
Nielsen 2005Study enrolled patients with active Crohn's disease
Sakurai 2002Study enrolled patients with active Crohn's disease
Seidman 2003Study enrolled patients with active Crohn's disease
Socha 2002Study enrolled patients with active Crohn's disease
Trebble 2004Study enrolled patients with active Crohn's disease
Trebble 2005Study enrolled patients with active Crohn's disease
Tsujikawa 2000Non-randomized study

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