ADALAIDE, Australia—An anti-inflammatory dose of fish oil, equivalent to about 2 tablespoons of conventional preparations, significantly improved levels of several biochemical markers linked to cardiovascular (CV) risk and reduced nonsteroidal anti-inflammatory drug (NSAID) requirements in a small study of patients with rheumatoid arthritis (RA). This was reported in the Journal of Rheumatology by Leslie G. Cleland, MD, and colleagues at the Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia.1
The investigators compared 13 patients who were taking combination chemotherapy for RA and chose not to take fish oil, with 18 patients on similar regimens who also took fish oil. The latter all achieved a sustained elevation of eicosapentaenoic acid (EPA) in plasma phospholipid fatty acids during the 3-year study.
All patients had RA symptoms for fewer than 12 months at study entry, and all were treated with methotrexate (MTX), hydroxychloroquine, and sulfasalazine. Doses of sulfasalazine and then of MTX were increased if the initial regimen did not provide adequate control of disease activity. Sequential addition of leflunomide and gold sodium thiomalate were used, if necessary. Oral steroids were not used. Acetaminophen was recommended for first-line treatment of pain, with NSAIDs as second-line treatment, if required.
Patients' cellular content of arachidonic acid (AA), synthesis of thromboxane A2 and prostaglandin E2, use of NSAIDs, traditional CV risk factors, and RA disease activity were assessed at baseline and at 3 years. Patients were examined at 3- to 6-week intervals initially and when they experienced disease flares. Once disease control was achieved, patients were assessed every 3 months. All patients in this report had completed at least 3 years of treatment.
The anti-inflammatory dose of fish oil used in this study was 4 g to 4.5 g EPA plus docahexaenoic acid (DHA) daily, taken either as bottled fish oil taken on juice or as capsules (7 x 1-g capsules twice daily).
Treatment Shifts Metabolism Away from Eicosanoid Synthesis
The subjects who did not take fish oil experienced no changes in plasma phospholipid fatty acids. In the 18 patients who did take fish oil, plasma EPA was >5% of total plasma phospholipid fatty acids throughout the study period, and mean EPA had increased from 1.2% to 8.2% of phospholipid fatty acids at 3 years. AA levels decreased, and EPA, docasopentaenoic acid, and DHA levels increased. "In between-group comparisons at 3 years, th[e] index of AA availability for eicosanoid synthesis was 30% lower in platelets and 40% lower in PBMC [peripheral blood mononuclear cells] of the fish oil group compared to the no fish oil group," the researchers write. They suspect that this results in inhibition of COX-1 and COX-2 activity.
NSAID use was also lower in the fish oil group (22% vs 54%, P <.05), and NSAIDs had been discontinued by 77% of the fish oil patients taking them at baseline, vs 37% of the control patients (P <.01).
At 3 years, all of the patients in the fish oil group but none in the control group had an erythrocyte omega-3 index above the threshold for low risk. At 3 years, the fish oil group also had significant improvements in total triglycerides, HDL cholesterol, and total cholesterol/HDL ratio (P <.05).
The fish oil patients also had better mHAQ scores, tender joint counts, erythrocyte sedimentation rates, and DAS28 scores at 3 years than did the control patients. The proportion of patients in remission at 3 years was 72% in the fish oil group vs 31% in the control group (P <.05).
According to Dr. Cleland, it would be reasonable to conclude from this study that adding anti-inflammatory doses of fish oil to the treatment regimen for patients with early RA should be considered as a step toward reducing CV risk.
This approach is being tested further in a larger, double-blind, randomized study. "The study involves comparison of a full anti-inflammatory dose of fish oil with a comparator oil [that] contains a small amount of fish oil sufficient to provide some cardioprotective effect but below the recognized anti-inflammatory dose, "Dr. Cleland told CIAOMed. "The test oils are given within the context of a predefined combination DMARD regimen for [patients with] early RA (<12 months), with predetermined rules for increasing treatment if disease suppression criteria are not met. Patients are randomized to fish oil or the comparator oil which contains the same flavorings. Patients and assessors are blinded to the allocation. The target for recruitment is 120 patients in total. The research question is whether the fish oil is a useful component of combination therapy for early RA, especially with regard to long-term outcomes, function, status, and structural changes."
Expert Advice on How to Drink Fish Oil
Intrigued by the data, your correspondent tested the regimen by drinking a glass of juice plus 2 tablespoons of fish oil and was inspired to ask Dr. Cleland whether compliance had been an issue. We wondered how the researchers had convinced patients to drink so much of this fishy beverage day in and day out for 3 years.
Dr. Cleland's advice: "At the dosage needed for an anti-inflammatory effect, capsules are unnecessarily expensive and inconvenient, hence the use of bottled fish oil taken on juice. The juice is layered on the fish oil in a small glass (~40 mL total volume), NOT stirred, and then swallowed quickly. This is followed by a small glass of juice alone, which is sipped slowly. The latter removes the fish oil from the mouth while the juice taste is still present. Taking the fish oil before a meal without extra fluid, but not on an entirely empty stomach, allows the fish oil to mix with food and to pass into the bowel without reflux, and therefore without any 'repeating' taste. Our preparation has a lemon-lime flavor added, but this is not essential as, with the above method, the fish oil can be taken without tasting it."
"With proper technique, for which we provide verbal and written instruction, compliance is not a major problem. About 20% of patients either are averse to the idea of taking fish oil or don't manage for other reasons. The long term continuation rates of about 80% are as good as with any of the medications we use. Fish-oil takers not infrequently comment that they get less reflux with bottled fish oil on juice than with capsules, even though the dose of fish oil taken is substantially greater than in the capsules they had been taking. When subjects talk of taking ‘fish oil in juice' rather than ‘on juice' and refer to use of a spoon, one should suspect that the fish oil is not being taken using the recommended technique," Dr. Cleland added.
Reference
1. Cleland LG, Gaughey GE, James MJ, et al. Reduction of cardiovascular risk factors with long-term fish oil treatment in early rheumatoid arthritis. J Rheumatol. 2006 Aug 01; [Epub ahead of print]