Various dietary fatty acids have been shown to have numerous immunomodulatory effects. Arachidonic acid (AA, 20:4 n-6) is synthesized in mammalian tissues from the essential fatty acid linoleic acid (18:2 n-6), found in many plant products. The release of AA from cell membrane phospholipids via the action of phospholipase A2 results in the subsequent production of AA-derived eicosanoids, such as prostaglandin (PG) E2 and leukotriene (LT) B4, which have potent proinflammatory and chemo-tactic effects. Alternatively, when AA is replaced with an n-3 fatty acid in the diet, such as eicosapen-taenoic acid (EPA, 20:5 n-3) or docosahexaenoic acid (DHA, 22:6 n-3), there is competitive inhibition of the use of AA as a substrate, and eicosanoids with different biological activity (PGE3 and LTB5) are produced through the cyclooxygenase and 5-lipoxy-genase cellular metabolic pathways (Figure 1). More specifically, EPA-derived eicosanoids result in decreased platelet aggregation, reduced neutrophil chemotaxis, and anti-inflammatory effects. Omega-3 fatty acids are derived primarily from marine sources, including fish and shellfish. Because modulation of dietary fatty acids can alter cellular eico-sanoid production, it has been hypothesized that increased consumption of n-3 fatty acids can affect the immunologic and inflammatory responses accompanying RA.
Dietary linoleic acid
Dietary a-linolenic acid
\ \ Arachidonic acid Eicosapontaenoic acid
PGH3 5-HPEPE -
Figure 1 Simplified diagram of eicosanoid formation. Enzymes are italicized. Key intermediates are in bold. COX, cyclooxygenase; 5-HEPE, 5-hydroxyeicosapentaenoic acid; 5-HETE, 5-hydroxy-eicosatetraenoic acid; 5-HPETE, 5-hydroperoxyeicosatetraenoic acid; 5-HPEPE, 5-hydroperoxyeicosapentaenoic acid; LT, leuko-triene; PG, prostaglandin; TX, thromboxane.
Eicosapentaenoic acid supplementation causes modest improvement in the number of tender joints and fatigue among patients with RA although clinical benefits have generally been small, subjective, and transient. Possible mechanisms for this improvement in clinical symptoms of inflammation include decreased LTB4 production, altered neutrophil membrane lipid composition, reduced interleukin-1 (IL-1) production, or a change in the a-tocopherol content of the diet. Overall, findings suggest that clinical benefits of dietary supplementation with n-3 polyunsaturated fatty acids (PUFAs) are more commonly observed among patients consuming higher dosages of fish oil, for longer periods than those previously studied. Indeed, beneficial clinical effects have been observed for as long as 1 year among patients with RA ingesting 2.6 g daily of n-3 PUFA supplements. In terms of optimal dosage of supplementation, however, a level of 130mgkg-1 day-1 (9g of n-3 PUFAs in a person weighing 70 kg) has been shown to result in no additional improvement compared with patients receiving doses ranging from 3 to 6g daily. Therefore, although the optimal level of fish oil supplementation is yet to be determined, there does appear to be an upper limit beyond which no additional benefit exists for patients.
Although some studies seem to suggest modest clinical improvements as a result of dietary fish oil supplementation in patients with RA, the question of the effects of a patient's medical regimen on the efficacy of fish oil supplementation remains. Non-steroidal anti-inflammatory agents are known to inhibit the cyclooxygenase enzyme system, which is the same pathway that seems to be inhibited by EPA and DHA. It is therefore possible that in studies of fish oil supplementation where patients are simultaneously maintained on NSAIDs, the effect of EPA is diminished, since the cyclooxygenase pathway is already inhibited by concurrent treatment with NSAIDs. Several studies have attempted to address this issue and have demonstrated a modest effect of n-3 fatty acid supplementation in both patients who are treated with NSAIDs and those who are not, suggesting that concurrent treatment with NSAIDs does not seem to diminish the effect of n-3 fatty acids. On the other hand, a clinically important NSAID-sparing effect of fish oil among patients who discontinue NSAIDs has not been demonstrated, suggesting that the benefits of fish oil supplementation are modest at best, relative to the effects of medication.
Although the majority of studies regarding manipulation of dietary fatty acids have focused on fish oil supplementation, other fatty acids have also been studied. The use of a-linolenic acid, the precursor of EPA and DHA, has not been shown to be of any benefit in RA. However, 7-linolenic acid, found in blackcurrent seed, evening primrose, and borage seed oils, has resulted in clinically important reductions in the signs and symptoms of disease activity in patients with RA, perhaps via a reduction in PGE2, IL-1, and IL-6. Because these oils do not cause an unpleasant fishy taste and odor in recipients, they may be preferred to fish oils for chronic treatment.
In summary, most studies of dietary supplementation with n-3 fatty acids suggest a modest improvement in clinical symptoms associated with RA, which are to some extent dose-and time-dependent. The most consistent clinical benefits have been reductions in tender joint counts and morning stiffness. Studies do not suggest that benefits are great enough to warrant discontinuing patients' other medications. However, the use of fish oil supplements, or diets rich in marine fish, may further improve clinical symptoms among patients with RA. Beyond the possible benefits in terms of controlling inflammatory symptoms of RA, increases in n-3 PUFAs are also associated with reduced risk of cardiovascular disease and other health benefits. Thus, there is reason to promote fish consumption among patients with RA consistent with general healthy eating recommendations. Both the American Heart Association and World Health Organization suggest consuming a minimum of two servings of fish per week, with one or more of the servings as oily fish. Those individuals who do not consume fish regularly may consider supplementation with modest levels of fish oils; however, until more is known about optimal dosages, caution should be taken with the use of concentrated high-dose fish oil supplements. Of note, there has been concern raised over environmental contamination of some types of marine fish with methylmercury. Therefore, eating a variety of fish will help to reduce any potentially negative health effects due to environmental contaminants.
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