It is clear that an increased intake of polyunsaturated fatty acids can improve their lipid profile [14]. Abundant experimental evidence supports the view that prostaglandins, thromboxanes, and leukotrienes (collectively termed eicosanoids), derived from polyunsaturated fatty acids, and participate in development and regulation of immunological and inflammatory responses [15–18]. The fatty acids themselves, by virtue of their incorporation into cell membranes and signal transduction elements, also have effects on cells involved in inflammation and immune responses that are independent of eicosanoids [18, 19]. A disease such as RA, characterized by abnormal immune responses, persistent inflammation, and joint tissue injury [20], may, therefore, be amenable to control by treatment with oils rich in specific polyunsaturated fatty acids.

Gamma-linolenic acid (GLA: 18:3 omega 6, see Figure 1) is an essential fatty acid found in certain plant seed oils, including borage seed oil. GLA is metabolized to dihomogamma-linolenic acid (DGLA; 20:3 omega 6), the immediate precursor of prostaglandin E₁ (PGE₁), an eicosanoid with anti-inflammatory and immunoregulatory properties [18]. In addition, GLA cannot be converted to inflammatory leucotrienes by 5-lipoxygenase. Instead, it is converted to 15-hydroxy-DGLA which has the additional virtue of suppressing 5-lipoxygenase activity [21]. GLA and DGLA also modulate immune responses in an eicosanoid-independent manner by acting directly on T lymphocytes [18] and GLA suppresses acute and chronic inflammation, including arthritis, in animal models [18]. In addition, fish oil, rich in eicosapentaenoic acid (EPA; 20:5 omega 3, see Figure 2) and docosahexanoic acid (DHA; 22:6 w-3), suppresses formation of the inflammatory eicosanoids PGE₂, thromboxane A₂ (TXA₂), and leucotriene B₄ (LTB₄). Randomized, placebo controlled double blind trials indicated that fish oil treatment of patients with RA result in clinical improvement, and those that monitored NSAID use suggest that fish oil treatment has an NSAID sparing effect [22].

The protocol was reviewed and approved initially by the Committee for the Protection of Human Subjects at the University of Massachusetts Medical School and the Food and Drug Administration. Subsequent approvals were obtained from the Review Boards at the University of Alabama, Geisenger Clinic, Fallon Health Care, and the New England IRB. Written informed consent was obtained from each patient.

Patients were eligible to participate in the study if they had RA according to the 1987 criteria of the American Rheumatism Association [25], were in functional class I, II or III according to the revised criteria of the American College of Rheumatology [26], and were between the ages of 18 and 85. Patients were on a stable dose of drugs for RA for at least 2 months before the screening visit and a total duration of therapy of at least 6 months. Doses of nonsteroidal anti-inflammatory drugs (NSAID) and/or prednisone (<10mg/d) were stable for at least 1 month before screening.

Patients were ineligible for the study if they had been treated with any investigational drug within 1 month of entry. If a patient was taking a fish oil supplement, the dose was stable and ≤2000mg/d for 2 months before screening. If a patient was taking a borage oil supplement, the dose was stable and ≤2000mg/d for 2 months before screening. An AST, ALT, or creatinine >1.5 times the upper limit of normal or a total bilirubin >1.8mg/dL excluded patients from the trial. Patients were instructed to maintain their typical diet.

The lipid profile was assessed at baseline, 9, and 18 months. Diet was assessed by 24-hour dietary assessment calls (24-HR), performed at baseline and 18 months. Both laboratory evaluation and 24-HR were obtained in most patients who dropped out of the study before 18 months and after 3 months. These results are included in the analysis, and were assigned to the closest 9-month interval to the date of patient's termination in the study.

Another 34 patients were screened but not randomized for the following reasons: arthritis medicine dose was not stable, too few tender joints, anticoagulated, high fish oil intake, high borage seed oil intake, medical issues, or abnormal laboratory values. The overall drop-out rate was 51% and was similar across groups: 25 in the borage oil group, 28 in the fish oil group, and 22 in the combination group. Reasons for dropout were mainly gastrointestinal distress (belching, bloating, diarrhea, nausea, cramping) or an inability to swallow the large number of rather sizable capsules.

Patient characteristics at baseline are presented in Table 1. The mean age of participants was 59 years and the sample predominantly female (80%). Most were white (90%), married (69%), and had a mean body mass index (BMI) of 30.5. An equal number were retired (33%) or working full time (34%), and 16% listed themselves as disabled. There were no significant differences between groups.

RA is a chronic systemic inflammatory disease. Mediators of inflammation and prothrombotic factors contribute to endothelial dysfunction and development of cardiovascular disease in RA patients [33]. There is little evidence that therapy for inflammation also leads to cardiovascular risk reduction in this group. Marine and botanical oils represent an excellent primary or secondary therapy for improvement of cardiovascular risk management in patients with rheumatoid arthritis.

Results of studies presented in this paper indicate that a GLA-enriched botanical oil (borage seed oil), an EPA/DHA-enriched fish oil, or a combination of these oils are useful for correcting dyslipidemia in patients with RA. Since there were no differences observed between the groups, with the notable exception of triglycerides and the AIP (shown separately in Table 3(b)), all 3 treatment groups were analyzed as a single group. Although lipid profiles of most patients were acceptable at baseline, patients taking these oils exhibit significant additional reductions in total and LDL cholesterol, triglycerides, the TC/HDL ratio, and the atherogenic index, and experience a significant increase in HDL cholesterol. All of these improvements in the lipid profile were seen after 9 months of therapy and increased after 18 months of oils administration. Particularly noteworthy is the group treated with both oils, as they experienced a significantly greater reduction in serum triglyceride concentrations and in the AIP than the groups on either oil alone. Oils enriched in GLA affect inflammation differently than oils enriched in EPA/DHA, and the anti-inflammatory and joint protective effects of the combination of these oils are synergistic in animal models [23]. Thus, it is possible that these different oils influence different aspects of TG synthesis or metabolism. Indeed, fish and botanical oils that provide EPA both reduce hepatic synthesis of TG in rats [34]. In humans the delta-5-desaturase that converts DGLA to arachidonic acid (AA) is sluggish, and we have not seen increases in circulating arachidonic acid after administration of GLA for 24 weeks [17]. Nonetheless, the possibility of increased circulating AA must be considered if treatment is to be long term. When fish oil is administered with borage oil to healthy individuals, bioconversion of GLA to AA is prevented [34], perhaps another reason for administering both GLA- and EPA-rich oils together.

All treatments were safe. Rates and types of adverse events were similar across all treatment groups, and as anticipated, were due entirely to mild to moderate gastrointestinal distress. The main reason for the large drop-out rate (in excess of 45%) was the large size and the number of capsules ingested each day over the 18-month-study period. It is possible to deliver much larger amounts of the individual polyunsaturated fatty acids (GLA, EPA, and DHA) in far smaller capsules than are needed to accommodate the natural marine and botanical oils, a strategy which should substantially reduce the dropout rate.

Alterations in diet can influence serum lipid concentrations [35]. However, the patients in our study did not change their diets over the course of the trial, suggesting that the improvements in their lipid profiles, including the significant increase in HDL cholesterol, are due to administration of the study oils. Most pharmacological treatments of dyslipidemia address reduction of LDL cholesterol [36, 37]. Since improvement in HDL cholesterol depends to a large extent on an exercise regimen [13, 38], many patients with RA are denied this manner of therapy. Thus, treatment with one or a combination of these oils could aid in the reduction of cardiovascular risk in RA patients whose disability impairs or prevents a prescribed exercise program.

Although LDL-C is the primary target of lipid-lowering therapy, other measures of the lipoprotein lipid profile, as reflected in the AIP and the TC/HDL-C ratios, are also associated with CVD risk. The AIP is a useful monitor of the lipid profile and its subsequent impact on the progression of cardiovascular risk [39]. In the study presented here, the AIP is significantly and beneficially altered at both 9 and 18 months compared to baseline. Patients in this study also exhibit a significant reduction in the TC/HDL ratio at 9 and 18 months, another indication of reduced CVD risk [40]. The safety of marine and botanical oils, and their remarkable impact observed in this study on the lipid profile of RA patients who are at increased risk for dyslipidemia and cardiovascular disease [1], suggest that these oils should have a prominent role in therapy of patients with RA.