Omega-3 Fatty Acids and Arthritis
By David Kiefer, MD. Dr. Kiefer recently completed a fellowship at the Program in Integrative Medicine, College of Medicine, University of Arizona in Tucson; he reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.
Omega-3 fatty acids (or n-3) are a type of poly-unsaturated fatty acid (PUFA) that has been known for many years to modulate inflammatory mediators, which has led researchers to explore the role of dietary and supplemental n-3 fatty acids in alleviating problems such as pain and arthritis. Sources as far back as 1783 mention how cod liver oil was used to treat musculoskeletal complaints1; this review will bring the topic up to date and discuss the evidence for the use of n-3 fatty acids in the treatment of rheumatoid arthritis (RA) and osteoarthritis (OA).
Sources of Omega-3 Fatty Acids
As detailed in a recent review for this journal,2 n-3 fatty acids are one of the family of fatty acids that make up polyunsaturated fats, and are either plant-based (α-linolenic acid, LNA) or marine animal-derived (eicosapentaenoic acid, or EPA, and docosahexaenoic acid, or DHA). LNA, the most common n-3 fatty acid in the American diet, is an essential fatty acid (as is α-linoleic acid, an n-6 fatty acid), that is, it is required in the human diet. LNA is found in flaxseed oil (8.5 g/Tbsp), flaxseeds (2.2 g/Tbsp), canola oil (1.3 g/Tbsp), soybean oil (0.9 g/Tbsp), English walnuts (0.7 g/Tbsp), and olive oil (0.1 g/Tbsp).3 In the human body, one of LNA's activities is to serve as a precursor primarily to EPA, but also to DHA, although the conversion to these longer-chain n-3 fatty acids is minimal.
Fish are the main dietary source of EPA and DHA. The concentration of EPA and DHA varies by the species of fish, the season, the packaging and cooking methods, whether it was farm-raised or wild (though wild and farmed salmon appear to be similar in this regard), and the diet of the fish.3 The highest n-3 concentrations appear to be in cold-water fish, such as (in order of decreasing EPA and DHA content) herring, sardines, salmon, mackerel, tuna, and halibut.4 For example, 15 g of mackerel or herring provides about 400 mg of n-3 fatty acids.5
Mechanism of Action
There are several possible mechanisms by which n-3 fatty acids could improve inflammation and therefore the symptoms associated with rheumatoid arthritis. The n-3 fatty acids EPA and DHA compete with arachidonic acid (AA, either directly ingested or metabolized from n-6 fatty acids) as substrates for metabolism by cyclo-oxygenase and lipoxygenase enzymes.6 AA leads to the formation of series 2 prostaglandins (PGs), series 4 leukotrienes (LTB4), and thromboxane A2, all of which are pro-inflammatory in the body, while n-3 fatty acids lead to the formation of series 3 PGs, series 5 leukotrienes (LTB5) and thromboxane A3, which are less inflammatory.1,6 LTB5 appears to be only 10% as active an inflammatory mediator as LTB4.7
Other inflammatory mediators may be involved. Animal and in vitro research demonstrates that fish oil in the diet can lower serum interleukins (IL-6, IL-10, IL-12) and tumor necrosis factor-alpha (TNF-α), suppress phospholipase C-mediated signal transduction, and inhibit the formation of leukotrienes (such as LTB4) from arachidonic acid via 5-lipoxygenase.1 In addition, fish oil seems to inhibit TNF-α and IL-1-beta through its inhibition of thromboxane A2 synthesis.6
Plant-derived n-3 fatty acids such as LNA may have some of the same effects, though research has found that fish oils achieve changes in tissue fatty acid composition, and presumably inflammatory responses, 2.5-5.0 times more effectively than LNA.8
Clinical Trials
There have been numerous clinical trials for both dietary interventions and supplemental n-3 fatty acids in people with RA. The main confounding factor with the results of these clinical trials is that most patients were instructed to continue their conventional medications, perhaps making it difficult to detect improvements from n-3 fatty acids.9 Also, most trials were done in the context of the standard Western diet, which is high in n-6 fatty acids, a situation that again would make it difficult for n-3 fatty acid supplementation to alter the n-3 to n-6 ratio sufficiently for a clinical effect; if the EPA to AA ratio is closer to 1, then there is a greater possibility of suppressing pro-inflammatory eicosanoids from AA.8 Despite these difficulties, one article reviewed 12 double-blind, placebo-controlled trials. Fish oil ingestion resulted in decreased joint tenderness, tender joint counts, and duration of morning joint stiffness after 12 weeks.9
For those studies measuring it, fish oil supplementation resulted in a decrease in nonsteroidal anti-inflammatory (NSAID) use. The doses ranged from 1.7 g daily of EPA plus 1.1 g daily of DHA, to 4.6 g daily of EPA plus 2.5 g daily of DHA. A meta-analysis agreed with these results, finding that three months of fish oil supplementation in 386 people led to improvements in tender joint counts and the duration of morning joint stiffness when compared to placebo, though the doses necessary to achieve these benefits is not mentioned in their analysis.10 The analysis also found no significant differences in parameters such as swollen joint count, grip strength, patient and physician assessment, or erythrocyte sedimentation rate.
Some of the individual trials illustrate the nuances in the literature for the use of fish oil in RA. For example, one double-blind crossover trial in 40 people with active RA compared 2.7 g of EPA plus 1.8 g DHA daily (in the form of 15 capsules daily of Max-EPA®) to an identical placebo (the contents of which are not mentioned), and requested that the patients continue their current medications and background diet.11 There were significant improvements in mean time to fatigue onset, the number of tender joints, and the reduction of neutrophil LTB4 with active treatment. However, this trial was not randomized, and only 33 people completed the trial with no evidence of an intention-to-treat statistical analysis, compromising final interpretation of the results.
In another double-blind, placebo-controlled trial, 66 patients with RA were randomized to receive either 200 mL of a flavored PUFA supplement or flavored liquid placebo for four months.12 The supplement contained 1.4 g of EPA, 200 mg DHA, and 940 mg of n-6 fatty acids, among other ingredients. The researchers found that the supplement group had increases in serum EPA, DHA, and vitamin E, but no statistically significant difference in tender joint counts or the other clinical parameters measured. Again, there was an issue with withdrawals (n = 11), a lack of intention-to-treat analysis, and the fact that patients continued their normal diet and medications, perhaps making an incremental treatment effect from n-3 fatty acids difficult to discern.
Another trial dosed the fish oil based on the subject's weight, and controlled for the background diet by putting subjects on a low n-6 fatty acid diet (< 10 g/d).13 Fifty patients were randomized to receive a fish oil supplement (40 mg/kg, 60% n-3 fatty acids) or placebo (half olive oil and half corn oil) for 15 weeks, and clinical evaluations were done at baseline and weeks 4, 8, and 15 for number of tender and swollen joints; global arthritis and visual analog pain scales were used. The researchers pooled the results for the different scales and clinical evaluations and found a modestly significant difference between the treatment and placebo groups only after 15 weeks of treatment. Of the 50 original patients, there were 24 withdrawals, primarily because of changes in regular medicines or noncompliance with treatment protocols; the withdrawals were not included in the analysis, seriously compromising the final results.
Another research trial extended the treatment period to 12 months.7 Sixty-four patients with NSAID-treated RA were randomized either to 10 fish oil capsules (Max-EPA with 171 mg EPA and 114 mg DHA per capsule) or air-filled placebo for one year followed by three months of placebo. Patients were instructed to slowly lower their NSAID dosing provided there was no exacerbation of their symptoms. Beginning at month 3 and persisting to month 15 there was a significant difference noted, in that subjects in the fish oil group were more successful in reducing reliance on their NSAIDs. No statistical differences were found for any of the clinical or laboratory values measured, though the EPA and DHA levels in red blood cell membranes were elevated in the fish oil group at months 6 and 12, and months 12 and 15, respectively. Also, arachidonic acid levels were lower in the treatment group at month 6. Again, withdrawals were an issue (27 total withdrawals).
One study investigated the use of LNA in RA, due to the fact that it is a precursor to EPA and DHA, and is often less expensive.14 Twenty-two patients with RA were randomized to 30 g daily of flaxseed powder (32% LNA) or a safflower oil powder placebo (33% linoleic acid) for three months. Assessments were made using global health scales, joint score indices, basic chemistry profiles, inflammatory markers, and fatty acid profile of serum phospholipids, palpatory pain testing, and subjective visual analogue pain scales. After three months, the flaxseed group had a higher serum LNA concentration, whereas the linoleic acid concentration was increased in the safflower oil group. None of the other parameters showed any difference between the two groups. The researchers speculated that perhaps this was due to the short length of the trial (though other three-month trials did have effects), or poor conversion of LNA to EPA and DHA.
Osteoarthritis
Though most clinical trials have focused on RA, there has been some interest in the use of n-3 fatty acids in osteoarthritis. One trial examined 10 mL daily of cod liver oil or 10 mL olive oil in 86 people with OA as diagnosed by their general practitioner (only 76% had the diagnosis corroborated by radiographs).15 The patients were assessed at baseline and every four weeks for joint pain and inflammation, overall interference with daily activities, and adverse effects, and patients were asked to use visual analog scales to assess pain and the extent to which the arthritis affected daily activities. The researchers found there was no difference between the olive oil group and the cod liver oil group with respect to these parameters. Limitations include the fact that not only was the placebo inadequate (olive oil has a different taste and itself has physiological effects), but more than 25% of patients dropped out and were not included in the final statistical calculations.
Dosage and Formulation
It is difficult to give specific suggestions for dosing based on the clinical trials, given that a variety of dosages have been tested in forms ranging from oils to capsules to powders. It is necessary to know the EPA and DHA content of supplements when dosing in line with the published clinical trials. For example, with 1 g fish oil capsules, which often contain 180 mg EPA and 120 mg DHA, it would be necessary to take approximately 10-15 capsules daily to achieve the dosages mentioned in most clinical trials and review articles (1.7-4.6 g daily EPA plus 1.1-2.5 g daily DHA). To avoid the toxic effects of some of the environmental contaminants of fish (see below), it is important to choose supplements that have been tested and shown to be free of methylmercury, polychlorinated biphenyls (PCBs), and dioxins; products should be labeled as being free of environmental contaminants, and this can be assured by checking with independent testing agencies such as ConsumerLab.com. Of note, there are some concentrated fish oil products that have elevated levels of EPA and DHA, decreasing the number of capsules required to achieve clinically useful amounts. The dose of LNA necessary to achieve similar results is difficult to predict due to the incomplete conversion of LNA to EPA and DHA in the body, and the fact that the one clinical trial failed to show an effect from LNA.
Adverse Effects, Contraindications, and Drug Interactions
In the clinical trials, adverse effects mentioned for the fish oil groups are comprised primarily of gastrointestinal symptoms such as loose stools, constipation, and belching, though in most cases these symptoms were also mentioned by the placebo groups at similar rates.11 There are concerns mentioned by some sources about increased bleeding time with use of fish oils, though no clinically significant abnormal bleeding events have been documented in the medical literature.16
N-3 fatty acids can cause an increase of approximately 5% in LDL cholesterol in some people; the elevation appears to be most pronounced in people with elevated triglycerides because fish oil may enhance the conversion of VLDL to LDL17; the additional LDL consists of the less pathogenic, larger, less dense LDL particles. Also, the effect of n-3 fatty acids is more pronounced in carriers of the apoE4 polymorphism, a trait that confers a greater tendency toward higher baseline serum cholesterol and risk of coronary heart disease; some people may respond with lipid changes more than others.18
There are concerns about contamination of fish with methylmercury, PCBs, and dioxins.16 Because of the dangers of these contaminants, the FDA and the Environmental Protection Agency recommend that women who might become pregnant, who are pregnant, or who are breastfeeding, and young children should not eat more highly contaminated fish species such as shark, swordfish, king mackerel, or tilefish, and should eat only 12 oz/wk of less contaminated fish species (canned light tuna, salmon, pollock, catfish).16,19 These dangers can be avoided by the use of tested fish oil products, the form of choice in the clinical trials for people with RA.
There are conflicting reports about whether n-3 fatty acids increase fasting glucose in people with diabetes. One randomized, double-blind trial investigated the use of 4 g/d of EPA, DHA, or olive oil placebo for six weeks in 59 people with Type 2 diabetes mellitus, and found a slight, but significant increase in fasting glucose of 1.4 and 0.98 mol/L in the EPA and DHA groups, respectively, when compared with placebo. There was no change in glycosylated hemoglobin, fasting insulin or C-peptide, insulin sensitivity or secretion, or blood pressure.20 This result is in contrast to other studies that have not found blood glucose elevations.21 These results should be taken in context of the possible cardioprotective effects of fish oils for people with diabetes.
Conclusion
There is a strong physiological basis for the use of n-3 fatty acids to mediate pain and inflammation, primarily by competing with arachidonic acid for metabolism through cyclo-oxygenase and lipoxygenase to yield less inflammatory eicosanoids such as the series 2 PGs and the series 4 LTs. There have been numerous clinical trials investigating the use of n-3 fatty acids in RA, as well as a meta-analysis, showing some clinical benefit primarily in the number of tender joints, the duration of morning joint stiffness, and the ability to reduce NSAID use, but these benefits seem to show up only after about three months of therapy. The most effective n-3 form seems to be fish oil dosed at 1.7-4.6 g daily EPA plus 1.1-2.5 g daily DHA. Caution is advised in people with elevated lipids; concerns about fish contamination can be addressed by taking purified, tested fish oil products.
Recommendation
There is reasonable evidence that n-3 fatty acid supplementation, in the form of fish oil, provides some clinical benefits to people with RA, and may even help them to reduce their use of NSAIDs. Given its safety profile, fish oil supplementation should be considered as an adjunctive therapy in RA patients willing to comply with the dosing (10-15 capsules daily is the most common form, but more concentrated products are available) and duration (at least three months) of therapy.
References
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Kiefer D. Omega-3 fatty acids and arthritis. Altern Med Alert 2005;8(11):127-131.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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