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From the Southern California Evidence-Based Practice Center, which includes RAND Health, Santa Monica, CA (CHM, WAM, SJN, RHG, WT, LGH, IMG, SR, PK, and SCM); the Greater Los Angeles VA Healthcare System Divisions of Rheumatology (CHM) and Gastroenterology (IMG), Los Angeles, CA; Clinical Decision Making and Healthcare, Toronto General Research Institute, Toronto General Hospital, Toronto, Ontario, Canada (JP); and the Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (JP)
2 The views expressed in this article are those of the authors and do not necessarily reflect those of the Agency for Healthcare Research and Quality (AHRQ) or the US Department of Health and Human Services. 3 Supported by AHRQ contract 290-02-0003. CHM and IMG are Veterans Administration Health Services Research and Development Career Development Awardees. 4 Address reprint requests to CH MacLean, RAND, 1700 Main Street, M23-C, Santa Monica, CA 90407-2138. E-mail: maclean{at}rand.org.
ABSTRACT
Background: n–3 Fatty acids are purported to have health effects in patients with inflammatory bowel disease (IBD), but studies have reported mixed results.
Objective: We aimed to synthesize published and unpublished evidence to determine estimates of the effect of n–3 fatty acids on clinical outcomes in IBD and whether n–3 fatty acids modify the effects of or need for treatment with other agents.
Design: Computerized databases were searched for studies of n–3 fatty acids in immune-mediated diseases from 1966 to 2003. We also contacted experts in the nutraceutical industry to identify unpublished studies; however, none were identified.
Results: Reviewers identified 13 controlled trials that assessed the effects of n–3 fatty acids on clinical, sigmoidoscopic, or histologic scores; rates of induced remission or relapse; or requirements for steroids and other immunosuppressive agents in Crohn disease or ulcerative colitis. Most clinical trials were of good quality. Fewer than 6 were identified that assessed the effects of n–3 fatty acids on any single outcome of clinical, endoscopic, or histologic scores or remission or relapse rates. Consistent across 3 studies was the finding that n–3 fatty acids reduce corticosteroid requirements, although statistical significance was shown in only 1 of these studies.
Conclusion: The available data are insufficient to draw conclusions about the effects of n–3 fatty acids on clinical, endoscopic, or histologic scores or remission or relapse rates.
Key Words: n–3 Fatty acids • inflammatory bowel disease
INTRODUCTION
n–3 Fatty acids have been promoted as conferring broad health benefits by preventing and treating a wide variety of diseases (1–3). In cell culture and animal studies, these essential fatty acids have potent immunomodulatory effects that appear to be mediated both through modulation of eicosanoid synthesis and through an eicosanoid-independent inhibitory effect on the proinflammatory cytokine interleukin 1 (IL-1). Thus, it has been proposed that supplemental n–3 fatty acids might be beneficial in treating or preventing relapse in chronic inflammatory diseases.
The inflammatory bowel diseases (IBDs), Crohn disease and ulcerative colitis, are diseases of altered immunity that affect >3.5 million persons in the United States and Europe and are associated with substantial morbidity (4–7). Population-based epidemiologic studies suggest that fatty acids may play a role in IBD (8, 9). Studies that have examined fatty acid profiles have shown decreased total serum polyunsaturated fatty acids in IBD patients as well as deficiencies specifically in n–3 fatty acids in Crohn disease patients (10, 11). Moreover, evidence exists that a proportion of IBD patients have essential fatty acid deficiency, which can contribute to the pathology of IBD (12). At the cellular level, IBD is characterized by elevated concentrations of IL-1 and proinflammatory leukotriene B (synthesized from n–6 fatty acids). Immunomodulatory mechanisms proposed for n–3 fatty acids in IBD include altering eicosanoid synthesis, cell membrane fluidity, cell signal transduction, intraluminal bacterial content, and gene expression (13).
Several clinical trials have been conducted to test the effects of n–3 fatty acid supplements on clinical outcomes in IBD. However, these studies have reported mixed results. We performed a systematic review of the literature to assess the benefits of n–3 fatty acid supplements in IBD. Our objective was to summarize what is known about the effects of n–3 fatty acids on clinical outcomes in IBD and to identify gaps in knowledge that will suggest the most fruitful direction for future research.
METHODS
The study on which this report is based is part of a larger systematic review of the medical literature regarding the effects of n–3 fatty acid supplementation on immune-mediated diseases. Consequently, our initial search was broad and sought data on the effects of n–3 fatty acids on IBD and several other immune-mediated diseases. The present report deals only with IBD.
Identification of the literature
Our search for studies that described the effects of n–3 fatty acids on IBD was combined with a search for studies of immune-mediated renal disease. The search terms we used were broad and were designed to identify any relevant human study (these are available from the authors on request). We did not restrict our searches by language or study design. The following databases were searched: MEDLINE (National Library of Medicine, Bethesda, MD; January 1966 through July 2003), PREMEDLINE (National Library of Medicine; searched on 8 July 2003), EMBASE (Elsevier, New York, NY; January 1980 through June 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Collaboration, Oxford, United Kingdom; searched 2nd Quarter Volume 2003), CAB Health (CAB International, Cambridge, MA; January 1973 through June 2003), and Dissertation Abstracts (Proquest, Ann Arbor, MI; January 1961 through December 2002). We identified additional literature by scanning the references of the relevant literature and by contacting industry experts for unpublished data.
Evaluation of the literature
We transferred the citations identified in our electronic literature search to a secured Internet-based software system that enabled us to view article titles and abstracts electronically. Two reviewers independently evaluated the citations and abstracts. At this stage, our goal was to identify articles that described studies of the effects of n–3 fatty acids on IBD in humans. Only titles that clearly did not meet these criteria were rejected; articles for which relevance was unclear from the title or abstract were considered to be relevant. All articles that were flagged as being relevant by at least one reviewer were obtained for further review. Language was not a barrier to inclusion.
Two reviewers independently reviewed each article by using a structured screening form. Studies were accepted for further review if they met the following predefined inclusion criteria: description of an intervention with n–3 fatty acids, human study population with IBD, and randomized controlled trial or controlled clinical trial, ie, experiments in which the use of n–3 fatty acids was under the control of the investigator, although trial participants might not have been randomly assigned to treatment groups. The reviewers resolved any disagreements by consensus.
Data extraction
For the articles that passed our screening criteria, 2 reviewers independently abstracted detailed data about the outcomes of interest; the number and characteristics of the patients; details on the intervention, such as the dose, frequency, and duration; the types of outcome measures; adverse events; and the elapsed time between the intervention and outcome measurements. To evaluate the quality of the design and execution of trials, we also collected information about the study design, appropriateness of randomization, blinding, description of withdrawals and dropouts, and concealment of allocation. All of these parameters have been validated as markers of methodologic quality either when used alone (14, 15) or when used in combination (14, 16).
All stages of the review were performed independently by 2 reviewers trained in health services research and the principles of critical appraisal; at least one reviewer was a physician. The reviewers resolved differences through consensus, and a senior physician researcher resolved any disagreements. Foreign language articles in languages in which one of our reviewers was fluent were reviewed by that reviewer alone. Other foreign language articles were reviewed by a physician fluent in the language of the article with the assistance of a study group member. We did not have interpreters available for 2 foreign language studies.
Outcomes of interest
The primary outcomes of interest were clinical, endoscopic, or histologic scores; rates of induced remission or relapse; or requirements for steroids or immunosuppressive agents. We included only articles that reported one or more of the outcomes of interest. For these outcomes, we assessed whether data were reported about the effects of n–3 fatty acids on subpopulations. We also assessed whether data were reported about the effects of source, dose, and exposure duration of n–3 fatty acids on the outcomes of interest.
Data analysis
For each of the studies identified, uniform data elements were summarized in evidence tables. For each study, the point estimates or magnitude of effect for each outcome of interest was summarized with a notation of the reported statistical significance of the result.
We calculated a quality score from 0 to 5 for each trial by using a system developed by Jadad et al (16). Studies with scores of 3 on this scale are considered high quality and tend to report smaller differences between treatment groups than studies with lower scores (14, 16). For our purposes, if the results of a trial were reported in more than one article, the quality score for that trial was the maximum score calculated across the various articles in which the study was described.
RESULTS
Literature search
The results of our literature search are detailed in Figure 1. We reviewed 366 citations and abstracts obtained from our computerized literature searches. We subsequently reviewed 6 additional titles identified by hand-searching the reference lists of accepted articles. We did not receive any unpublished data regarding IBD and n–3 fatty acids in response to our requests to industry experts. Our 2 reviewers considered 180 of the article titles to be relevant. We were able to retrieve all but one of the 180 titles as full-text articles.
FIGURE 1.. The results of the literature search. *One article reported outcomes for both Crohn disease and ulcerative colitis.
Of the 179 articles retrieved, 114 pertained to the use of n–3 fatty acids in the treatment of IBD in humans; among these 114 articles, 24 reported on randomized controlled trials or controlled clinical trials and underwent a more detailed review. On detailed review, 3 of the 24 articles did not define a difference in n–3 content across study arms, 6 did not study outcomes of interest, 1 was a duplicate report of information included in another article, and 1 did not report the data separately for each study arm. Each of the remaining 13 articles described outcomes of interest to this review; 2 of these articles described different outcomes of the same study (17, 18).
Study characteristics
The characteristics of each study are summarized in Table 1. Methodologic quality varied among the 12 studies described in the 13 articles we reviewed. Jadad scores were 3 for 7 of the 12 studies; the mean Jadad score was 3.2. Concealment of allocation was reported in 3 of the 12 studies.
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TABLE 1. Characteristics of identified studies of the effects of n–3 fatty acids in inflammatory bowel disease1
Summary of effects
The effect of n–3 fatty acids for each study across all outcomes assessed are summarized in Table 2 (17–29).
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TABLE 2. Summary of effects of n–3 fatty acids on clinical scores, endoscopic scores, histologic scores, relapse, remission, and corticosteroid requirements in inflammatory bowel disease1
Clinical score
Clinical score for ulcerative colitis was assessed in 4 studies through the use of either the ulcerative colitis activity index (30) or the disease activity index (31); a fifth study used a "clinical score" that was not otherwise described. Study duration for the 5 studies ranged from 3 to 24 mo. Three of the 5 studies reported statistically significant improvement with n–3 fatty acids relative to the comparative study arm at one or more time points (19, 20, 23, 29); one of those 3 studies, however, reported no effect at the predetermined study endpoint (23; Table 3). Among the 2 studies that reported improvement at the predetermined study endpoint, one reported improvement at 3 mo (20) and one reported improvement at 6 mo (29). In all cases, the magnitude of effect was small. Among the 2 studies that did not report significant differences between n–3 fatty acids and placebo, one explicitly reported testing for differences between groups and found none at the predetermined study endpoint of 3 mo (24). The other study did not explicitly report testing for differences between groups but showed no significant differences at any time point between 0 and 6 mo through overlapping CIs displayed on a graph (19).
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TABLE 3. Reported effects of n–3 fatty acids on clinical scores in inflammatory bowel disease by study population
One study reported a clinical score for Crohn disease, as measured by the Crohn's Disease Activity Index (32). This study found no significant difference in the index between subjects treated with n–3 fatty acid capsules and subjects treated with olive oil capsules (24; Table 3).
Endoscopic score
Endoscopic score was reported for ulcerative colitis in 3 studies (19, 24, 29) and for Crohn disease in one study (24). Each of the 2 studies that were restricted to patients with ulcerative colitis (19, 29) reported a statistically significant improvement with n–3 fatty acids relative to the comparative treatment (Table 4). The other study included both patients with ulcerative colitis and those with Crohn disease (24). In that study, n–3 fatty acids were associated with a statistically significant improvement relative to the comparative treatment when all patients were included in the analysis; differences were not significant when analyses were restricted to either ulcerative colitis or Crohn disease. We note that the discrepancy between the restricted and combined results may be due to either a type II error occurring in the restricted results or a type I error occurring in the combined results.
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TABLE 4. Reported effects of n–3 fatty acids on endoscopic scores in inflammatory bowel disease by study population
Histologic score
Histologic score was reported for ulcerative colitis in 3 studies. Two reported no significant difference between groups (20, 22) and one reported a statistically significant improvement (19; Table 5). Histologic score was not reported in any of the studies of Crohn disease.
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TABLE 5. Reported effects of n–3 fatty acids on histologic scores in ulcerative colitis
Remission
Induction of remission was reported for ulcerative colitis in one study, (19) and maintenance of remission was reported in another (17). Neither study showed significant differences in remission between the n–3 and comparative groups. In one of the studies (19), comparable data for the placebo group were not reported. Remission was not reported in any of the studies of Crohn disease (Table 6).
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TABLE 6. Reported effects of n–3 fatty acids on relapse and remission in inflammatory bowel disease by study population
Prevention of relapse
None of the 5 studies (23) that examined relapse for ulcerative colitis found significant differences between n–3 fatty acids and placebo (17, 22, 23, 26, 27; Table 6). Two studies assessed relapse for Crohn disease. One reported a significantly lower relapse rate with n–3 fatty acids than with placebo (21), whereas the other study found no significant difference in the rate of relapse between groups (25; Table 6). Of note, the study that found a significantly lower relapse rate administered the fish oil via an enteric-coated capsule that was designed to deliver the n–3 fatty acids to the small bowel (21).
Requirement for immunosuppressive agents
We identified 3 studies in 4 articles that assessed the effect of n–3 fatty acids on requirements for corticosteroids in ulcerative colitis and none in Crohn disease (17–19, 28; Table 7). We did not identify any studies that assessed the effect of n–3 fatty acids on requirements for other immunosuppressive agents in either ulcerative colitis or Crohn disease. Two studies in 3 articles (17, 18, 28) described changes in daily steroid doses. In 1 study in 2 articles (17, 18), the reduction in the median daily prednisolone dose during the study period was greater among the subjects treated with n–3 fatty acids than among the subjects treated with placebo (P = 0.01). In another study (28), the mean prednisone dose was lower among subjects treated with n–3 fatty acids and was higher among subjects treated with placebo; however, the changes within each group were not significant, and the significance of the differences across groups was not reported. Two studies described the number of patients who required treatment with corticosteroids (19, 28). In one (19), fewer patients treated with n–3 fatty acids required prednisolone enemas or systemic corticosteroids than did patients treated with placebo. In the other study (28), the number of patients for whom daily steroid dose could be reduced was greater for n–3 treatment than for placebo (statistical testing for this comparison not reported).
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TABLE 7. Reported effects of n–3 fatty acids on immunosuppressive drug requirement in ulcerative colitis
Effects of source, dose, and exposure duration
All identified studies used fish oil as the source of n–3 fatty acids. No studies compared the effect of different doses of n–3 fatty acids. Too few studies assessed the effects on any single outcome to perform a meta-analysis of dose effect. Duration of exposure varied from 2 to 24 mo across the studies. Too few studies assessed any single outcome across similar time periods to analyze the effect of duration of exposure.
DISCUSSION
The available data are insufficient to draw conclusions about the effects of n–3 fatty acids on clinical, endoscopic, or histologic scores; induced remission; relapse rates; or requirements for immunosuppressive therapy in IBD. Many of the individual studies were underpowered to detect clinically significant effects, and across studies, the data were insufficient data to draw conclusions about any individual outcome assessed. Viewing the outcomes together across individual studies, 3 studies reported significant benefits with n–3 fatty acids on 2 of the outcomes assessed. However, the methodologic quality of 2 of these studies was not optimal. Hence, we found little evidence within or across studies to suggest that n–3 fatty acids are beneficial in the treatment of IBD. However, the observed efficacy of n–3 fatty acids when delivered by enteric coated capsule and the findings that pertain to the effect of n–3 fatty acids on steroid requirements warrant discussion.
Although 7 of 8 trials that assessed the effect of n–3 fatty acids on remission or relapse found no effect (17, 19, 22, 23, 25–27), the single trial that did find an effect differed from the other trials in that it used a unique system for the delivery of n–3 fatty acids (21). This well-designed study found a markedly lower relapse rate for the fish oil group than for the control group (28% compared with 69%; P < 0.001). That the other studies did not find an effect on relapse rate suggests that the observed effect resulted from delivering the fish oil to the diseased area of the bowel. Further studies are needed to confirm this finding.
Also of note are the findings that pertain to the effect of n–3 fatty acids on steroid requirements. The identified studies suggest that fewer patients taking n–3 fatty acids required corticosteroids, and among the patients who did require corticosteroids, doses were lower or could be lowered while the patients were being treated with n–3 fatty acids relative to placebo. Among individual patients in one study (28), the mean prednisone dose was reduced during treatment with fish oil for 5 patients (71%), discontinued for 2 patients (29%), and increased for 1 patient (14%); during treatment with placebo, the mean dose was reduced for 1 subject (14%), discontinued for none, and increased for 3 (43%). However, the size was small and the difference between groups was not significant.
More striking than the information pertinent to our study questions was the paucity of information on many variables that are important to understanding the effects of n–3 fatty acids in IBD. First, because differences in dose, source, and type of n–3 fatty acid may affect clinical outcomes, information on these variables would inform our knowledge about the effects of n–3 fatty acids (28). However, too few of the studies we reviewed reported these variables to allow us to draw any conclusions about the effects of dose, source, or type of n–3 fatty acid. Second, because baseline dietary consumption of n–3 and n–6 fatty acids may influence the effects of supplementation with n–3 fatty acids, trials of n–3 fatty acids should include an assessment of total dietary n–3 and n–6 fatty acid intake. However, only one of the studies that we identified did so (17). In that study, total dietary intake of 20:5 and 22:6 fatty acids was significantly higher in the intervention group during supplementation. Third, because n–6 fatty acids may be proinflammatory and most of the studies reviewed substituted n–6 fatty acids with n–3 fatty acids, observed effects could be the result of reducing absolute n–6 fatty acid intake rather than increasing n–3 fatty acid consumption. Finally, the present review may be limited by selective reporting of outcomes in the studies reviewed. Recent empiric data have shown that statistically significant outcomes are more likely to be reported than nonsignificant outcomes (33). It is worth noting that among the 3 studies that described the effects of n–3 fatty acids on steroid use, steroid use was not described as a primary outcome in any. It is not known whether secondary analyses of steroid use that identified only insignificant results were not reported.
The conclusions that can be drawn from the present review are limited by the paucity of literature that we identified that described the effects of n–3 fatty acids on IBD. Because our search methods were comprehensive, this apparent lack of published literature likely represents an actual paucity of research on this topic.
On the basis of a comprehensive literature review, the available data are insufficient to draw conclusions about the effects of n–3 fatty acids on clinical, endoscopic, or histologic scores or induced remission or relapse rates. However, the data that pertain to the effects of n–3 fatty acids on steroid requirements suggest that n–3 fatty acids may reduce the need for or effective dose of corticosteroids among patients with IBD. Future studies should assess the effects of n–3 fatty acids on clinical outcomes in IBD, including requirements for corticosteroids.
ACKNOWLEDGMENTS
We thank Paul Shekelle for his review of the manuscript and Shana Traina for her help in preparing the manuscript.
CHM was the principal investigator, conceived the study design, supervised data collection and abstraction, and drafted the manuscript. WAM provided critical input for the design of this study and reviewed and abstracted articles. SJN provided critical input on interpretation of data and the writing of the manuscript. JP provided critical input for the design of this study and reviewed and abstracted articles. RHG oversaw the collection of data. WT abstracted study data. LGH produced and maintained the study data files. IMG provided critical input on the interpretation of studies and the early versions of the manuscript. SR helped to collect and track data. PK provided critical input on the design of this study, reviewed and abstracted articles. SCM provided critical input on the design of this study and interpretation of data. All authors took part in the discussion of the results and approved the final version of the manuscript. None of the authors had any conflicts of interest.
REFERENCES