Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S, Miglioli M. New England Journal of Medicine, 1996, Volume 334, Number 24, pages 1557-1560. DOI: Not available.
Background & Rationale
Crohn’s disease features remission periods interrupted by relapses, with recurrence risk greatest shortly after achieving remission, particularly in patients with elevated acute-phase proteins. Fish oil possesses antiinflammatory properties through reduced leukotriene B4 and thromboxane A2 production, cytokine inhibition, and free-radical scavenging. However, conventional preparations are poorly tolerated due to unpleasant taste and gastrointestinal effects. The authors developed a novel enteric-coated fish-oil preparation achieving high omega-3 absorption at one third the previously required dose, potentially improving tolerability.
Study Design
This one-year randomised, double-blind, placebo-controlled trial (May 1992 to September 1993) enrolled 78 patients with Crohn’s disease in clinical remission. Patients received either nine enteric-coated fish-oil capsules (2.7 g omega-3 fatty acids: 1.8 g eicosapentaenoic acid, 0.9 g docosahexaenoic acid) or identical placebo capsules daily. Eligible patients had Crohn’s Disease Activity Index scores below 150 for three months to two years, plus at least one elevated inflammatory marker. The primary endpoint was clinical relapse, defined as activity index increase of at least 100 points above baseline and score above 150 for over two weeks. Patients were assessed at 3, 6, 9, and 12 months. Statistical analysis employed chi-square tests, Mann-Whitney U tests, Kaplan-Meier survival analysis, and multivariate logistic regression.
Patient Population
Baseline characteristics were balanced. The fish-oil group comprised 39 patients (median age 34 years, 20 male, 14 smokers, median disease duration 68 months, 14 previous resections). The placebo group comprised 39 patients (median age 39 years, 19 male, 13 smokers, median disease duration 66 months, 13 previous resections). Median remission duration was 7 to 8 months in both groups.
Key Findings
Fish oil demonstrated significantly lower relapse rates: 11 of 39 patients (28 per cent) relapsed versus 27 of 39 placebo patients (69 per cent), a 41 percentage point difference. After one year, 23 fish-oil patients (59 per cent) remained in remission versus 10 placebo patients (26 per cent). Four fish-oil patients withdrew due to diarrhoea versus one placebo patient. Multivariate analysis identified fish-oil treatment as the sole significant predictor of relapse prevention (odds ratio 4.2 for placebo versus fish oil). Among relapsing patients, symptoms were similar: diarrhoea (85 to 91 per cent), moderate or severe abdominal pain (91 to 93 per cent), poor general condition (100 per cent). All required methylprednisolone treatment.
Discussion
Fish oil may exert antiinflammatory effects through multiple mechanisms including reducing inflammatory mediators elevated in Crohn’s disease mucosa, inhibiting cytokine synthesis, scavenging free radicals, and inhibiting platelet responsiveness. The enteric coating resists gastric acid for 30 minutes, releasing contents in the small intestine and reducing gastric side effects. Eicosapentaenoic acid levels increased 2,800 per cent and docosahexaenoic acid 360 per cent in fish-oil patients, whilst arachidonic acid decreased 48 per cent. Inflammatory markers decreased significantly in the fish-oil group: erythrocyte sedimentation rate decreased 20 per cent versus increasing 14 per cent with placebo. Ten per cent discontinued due to diarrhoea, possibly from slower capsule breakdown in patients with short intestinal transit times. Safety monitoring revealed no other concerns.
Authors’ Conclusions
The authors concluded that this enteric-coated fish-oil preparation effectively reduces relapse rates in Crohn’s disease patients in remission, demonstrating few gastric side effects and high compliance. Omega-3 absorption and phospholipid membrane incorporation was high. Efficacy relative to mesalamine, the standard maintenance treatment, remains to be determined. Results are particularly relevant for high-risk patients with recent remission and abnormal inflammatory markers.
Later Evidence
This trial’s striking result was not replicated in subsequent, larger studies. Two later multicentre randomised controlled trials, EPIC-1 and EPIC-2 (over 700 patients combined), found that omega-3 fatty acids offered no benefit in preventing relapse of Crohn’s disease (Feagan BG, Sandborn WJ, Mittmann U, et al. Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC Randomized Controlled Trials. JAMA. 2008;299(14):1690-1697). A 2014 Cochrane systematic review concluded that omega-3 fatty acids probably have little or no effect on maintaining remission in Crohn’s disease (Lev-Tzion R, Griffiths AM, Leder O, Turner D. Omega 3 fatty acids (fish oil) for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2014;2014(2):CD006320). This 1996 trial’s positive result is now considered an outlier rather than representative of fish oil’s likely effect.
Reference
Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S, Miglioli M. Effect of an enteric-coated fish-oil preparation on relapses in Crohn’s disease. N Engl J Med. 1996;334(24):1557-1560.
This Scientific Publication Summary is an objective summary of the published trial for personal and educational use. It does not constitute clinical advice, endorsement of the intervention, or a recommendation to alter clinical practice.