immune modulation by parenteral fish oil in patients with crohn's disease

Conditions: Crohn Disease

Summary: to evaluate the effects of infusion of a fish oil-based lipid emulsion on tnf-α production and other relevant immune functions. a soybean oil emulsion, rich in the omega-6 polyunsaturated fatty acid linoleic acid, will serve as control.

rationale: fish oil (fo), rich in omega-3 polyunsaturated fatty acids, exerts a range of anti-inflammatory actions that render it a potential therapeutic agent to treat crohn's disease, a chronic inflammatory disease that primarily affects the bowel. recent evidence suggests that a lack of effect in previous studies might be due to the fact that genetic background was not taken into account. for instance, a study in healthy subjects showed that production of the pro-inflammatory cytokine tumor necrosis factor-alpha (tnf-α) following fo supplementation decreased in individuals within the highest tertile of pre-supplementational tnf-α production, remained unaltered in the middle tertile, and increased in the lowest tertile of pre-supplementational tnf-α production. tnf-α plays a pivotal role in the pathogenesis of crohn's disease, hence the treatment with anti-tnf-α agents. based on these notions, and because fo supplementation via the enteral route is strongly dose limited due to fat-induced side effects such as diarrhea, we hypothesize that parenteral fo supplementation might be beneficial in those patients with crohn's disease with a high inherent tnf-α production. study design: single center, randomized, single blinded, lipid-controlled, cross-over pilot trial. study population: adult patients with crohn's disease with previous bowel surgery, currently in remission (without the need for immunosuppressive drugs) and with a high inherent tnf-α production. intervention: first, patients with a high inherent tnf-α will be identified by assessment of tnf-α production in a group 100 patients who meet in- and exclusion criteria. patients within the highest tertile will be classified as high producers. next, 5 patients within the highest tertile will be randomized to receive intravenous administration of 20% (w/v) lipid-control (intralipid®), and, after crossing over, 10% (w/v) fish oil emulsion (omegaven®), or vice-versa for 1 hour on three consecutive days at a dose of 0.2 g/kg bodyweight /hr. study parameters will be assessed in blood drawn prior to the first infusion (t=0) and 1 (t=4) and 8 days (t=11) after the third infusion. between the two treatment arms, there will be a wash-out interval of at least 2-3 weeks. main study parameters/endpoints: early (t=day 4) and late (t=day 11) effects of infusions on tnf-α production by whole blood cultures. secondary outcomes: effect on leukocyte counts, leukocyte functions and on (anti-)oxidant status, the occurrence of oxidative damage and analysis of specific single nucleotide polymorphisms (snps) related to tnf-α production.

Eligibility criteria:
inclusion criteria: * adult patients with crohn's disease with previous bowel surgery, currently in remission (without the need for immunosuppressive drugs) and with a high inherent tnf-α production. exclusion criteria: * patients with other active inflammatory / immune mediated underlying diseases * smoking \> 5 cigarettes a day * diet with \>2 portions of fatty fish (tuna, salmon, mackerel, herring, and trout) a week * history of metabolic disorder (especially diabetes or lipid disorders) * crohn's disease activity, including the presence of active fistulas * on need for medical (other than 5-aminosalicylic acid preparations) or surgical treatment for crohn's disease activity * use of non-steroidal anti-inflammatory drugs or aspirin * c-reactive protein levels of \>10 mg/l * history of venous or arterial thrombosis * active malignancy * presence of severe pulmonary, cardiovascular, renal, liver, coagulation or hematological disease * pregnancy or lactation * age \<18 yrs * allergy for one of the following components: fish, chicken, eggs or soy beans