Summary

Supplementation with fish oil may be beneficial for some patients with rheumatoid arthritis (RA) due to its mild anti-inflammatory effects.1 The benefits that have been reported among this patient group include an improvement in pain and reduction in the use of non-steroidal anti-inflammatory drugs (NSAIDs).

Practice points

  • Supplementation with omega-3 (n-3) polyunsaturated fatty acids (PUFAs) has been shown to improve pain and reduce NSAID use in some patients with RA.
  • Studies suggest that an intake of 2.7 g/day of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) is required to achieve anti-inflammatory effects in patients with RA.
  • Despite these reported symptomatic benefits, fish oil supplementation should not replace conventional therapy such as disease-modifying antirheumatic drugs (DMARDs).

RA is a chronic inflammatory autoimmune condition characterised by pain, swelling and destruction of the synovial joints resulting in disability.2 Although the exact cause of RA is unknown, symptoms are to some extent a result of local production of pro-inflammatory eicosanoids such as prostaglandin E2 and leukotriene B4.3

The aim of modern treatment strategies is to induce disease remission through early and aggressive use of DMARDs. These medicines are often used in combination with other therapies to reduce joint inflammation and destruction in patients with RA. Conventional synthetic DMARDs are the first-line treatment in RA, with methotrexate recommended as the gold standard.1

Despite the effectiveness of DMARDs, other therapies are routinely prescribed to help patients manage symptoms. These include NSAIDs and complementary therapies such as fish oil supplements.1

What do we know about fish oil supplements? 

Marine fish oil is rich in long-chain n-3 PUFAs which contain 18% EPA and 12% DHA.3 Fish oil supplements can take the form of capsules or liquid and the amount and relative proportion of n-3 fatty acids can vary between supplements.4

The n-3 PUFAs in fish oil have been shown to modify immunological responses involved in the pathophysiology of RA, including T-cell reactivity, reactive oxygen species reduction by leucocytes and inflammatory cytokine production by macrophages.5

EPA and DHA have been shown to suppress synthesis of eicosanoids including prostaglandin E2 and leukotriene B4, two of the most important pro-inflammatory mediators involved in RA. The omega-6 (n-6) PUFA arachidonic acid (ARA) is responsible for the production of these eicosanoids through the enzyme cyclooxygenase (COX). EPA and DHA found in fish oils decrease the ARA content of immune cells and produce less inflammatory eicosanoid mediators than those produced by ARA.5

Benefits for joint pain and stiffness

Positive effects of fish oil supplementation on various disease outcomes including joint pain and stiffness have been reported in patients with RA. Fish oil may take up to 3 months to exert a maximal effect, so it may be necessary to prescribe fish oil supplements alongside NSAIDs initially.

A systematic review evaluating the effect of marine fish oil on pain in arthritic disease concluded that patients with RA experienced a reduction in pain (standard mean difference [SMD] –0.21, 95% confidence interval [CI] –0.42 to –0.00) with low heterogeneity observed between studies (I2 = 32%).6

Beneficial outcomes have also been reported in a meta-analysis of randomised controlled trials where supplementation with n-3 PUFAs for 3–4 months reduced patient reported joint pain intensity (SMD −0.26, 95% CI −0.49 to −0.03, p = 0.03), the amount of morning stiffness (measured in minutes) (SMD −0.43, 95% CI −0.72 to −0.15, p = 0.003) and the number of painful and/or tender joints (SMD −0.29, 95% CI −0.48 to −0.10, p = 0.003). Although significant, these differences are very small. Taking a fish oil supplement did not impact doctor-assessed pain (SMD −0.14, 95% CI −0.49 to 0.22, p = 0.45).7

Reducing the need for treatment

NSAIDs are often recommended for short-term pain relief in patients with RA. These medicines exert their analgesic effects by inhibiting COX, an enzyme responsible for pain and inflammation.3 As their use is associated with increased risk of upper gastrointestinal and CV events, NSAIDs should be used in the lowest dose possible needed to reduce pain, and for short periods only.8,9 A meta-analysis concluded that n-3 PUFAs at doses > 2.7 g/day for > 3 months significantly reduced NSAID use in patients with RA (SMD –0.518, 95%, CI –0.915 to –0.121, p = 0.011) with no heterogeneity between studies (I2 = 0%).3

The effects of cod liver oil supplementation on NSAID requirements in patients with RA are also promising.10

Reducing corticosteroid use

Corticosteroids are routinely prescribed alongside DMARDs in the treatment of RA for their anti-inflammatory and disease-modifying effects. Due to their rapid onset of action, corticosteroids offer rapid symptom control in patients awaiting a response from DMARD therapy. However, they should only be used temporarily as significant adverse effects limit their long-term use.1

There is some evidence to suggest that fish oil supplementation can reduce the use of corticosteroids for symptomatic management in patients with RA.5,11

Does dose or supplement type matter?

Studies suggest that there may be a dose response relationship between marine n-3 PUFAs and the reduction of ARA-derived eicosanoids associated with inflammation. To elicit an anti-inflammatory effect, a threshold intake of 2.7 g per day EPA has been suggested.5,9 Studies using low intakes of EPA and DHA (< 1.5 g/day) have not concluded any clinical benefit from fish oil supplementation.5

Other studies have made similar conclusions, observing symptomatic benefits with doses above 2.7 g per day after a delay of 2–3 months.12,13 However, participants in these studies had established disease (average duration 10.2 +/– 5.2 years) and were subject to study withdrawal if treatment variation was required. These limitations are problematic for interpreting the effect of fish oil supplementation in modern RA treatment.13

Some studies have also suggested that the type of n-3 PUFA may have some impact on clinical efficacy, with EPA more effective than DHA in improving disease outcomes in patients with RA. In a systematic review, a significant, beneficial effect on joint pain was observed for fish oil with an EPA/DHA ratio > 1.5, suggesting that EPA is more beneficial than DHA.6

With this evidence in mind, a threshold intake of at least 2.7 g (n-3) daily is recommended in clinical guidelines in order to achieve a mild anti-inflammatory effect in patients with RA.

Safety considerations

Although a dose of 3 g/day EPA plus DHA is considered safe for general consumption, further clarification around the safety profile of fish oil supplements in the RA population is required.4,12 PUFA supplementation, particularly at high doses, has been associated with gastrointestinal intolerance (eg, ‘fishy’ aftertaste, heartburn and diarrhoea), mercury contamination and prolonged bleeding time.4

Extra caution should be taken with fish liver oils such as cod liver oil due to the risk of vitamin A toxicity. Anti-inflammatory doses of cod liver oil can contain higher levels of vitamin A than the recommended intake. Fish body oils, which contain minimal amounts of vitamin A, are a more suitable option.12

Conclusion

Due to its mild anti-inflammatory effects and low risk of harm, fish oil supplementation is a reasonable treatment option for RA patients with mild residual joint pain. Meta-analyses provide evidence for the symptomatic benefits of fish oil supplementation in RA; however, gastrointestinal intolerance is a barrier to treatment and is a common side effect of the high doses that are needed to elicit an anti-inflammatory effect in RA. 

Future clinical trials could benefit from studying the use of fish oil supplementation in patients with recent-onset RA and by using study designs which better reflect the aims of modern RA treatment.14 Further evidence is also required in order to establish an optimal dose and ratio of EPA and DHA in fish oil supplements for the management of RA.

Information for patients

Omega-3 fatty acids found in marine fish oil may help to reduce inflammation in the joints and improve the symptoms of rheumatoid arthritis in some people. Having less severe symptoms may allow you to reduce the doses of other medicines you take for rheumatoid arthritis. Fish oil supplements may take up to 3 months for maximal effectiveness, so you may need to take other pain relief medicines in the meantime. These include non-steroidal anti-inflammatory drugs (eg, aspirin, ibuprofen, diclofenac) and steroids (eg, prednisone). However, it is important that you do not stop taking your other medicines or reduce the doses without speaking to your doctor first.

Supplements vary in the amount of omega-3 they contain. If you have rheumatoid arthritis the recommended daily intake of omega-3 in fish oil is at least 2.7 g. This is the same as taking between 6 and 9 capsules or 1–3 teaspoons of liquid per day. Serious side effects from fish oil supplements are rare at these doses but minor side effects may include nausea and a rash.

Gastrointestinal adverse effects of fish oil include heartburn, diarrhoea and a fishy aftertaste. . Taking the capsules with food or keeping them in the freezer can help reduce this aftertaste.

Extra caution should be taken with fish liver oils such as cod liver oil as they contain high levels of vitamin A. High intake of vitamin A in the diet can be toxic. For this reason, take omega-3 supplements from fish body oil rather than fish liver oil. 

References

  1. Rheumatology Expert Group. Therapetic Guidelines: Rheumatoid arthritis. West Melbourne: Therapeutic Guidelines Ltd, 2017 (accessed 29 January 2018).
  2. Smolen J, Aletaha D, Koeller M, et al. New therapies for treatment of rheumatoid arthritis. The Lancet 2007;370:1861-74.
  3. Lee Y, Bae S, Song G. Omega-3 polyunsaturated fatty acids and the treatment of rheumatoid arthritis: a meta-analysis. Arch Med Res 2012;43:356-62.
  4. Whittle S, Richards B, Ramiro S, et al. Fish oil supplements for rheumatoid arthritis. Cochrane Database Syst Rev 2012.
  5. Miles E, Calder P. Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic reviw of their effects on clincal outcomes in rheumatoid arthritis. Br J Nutr 2012;107:S171-84.
  6. Senftleber NK NS, Andersen JR, et al. Marine Oil Supplements for Arthritis Pain: A Systematic Review and Meta-Analysis of Randomized Trials. Nutrients 2017.
  7. Goldberg R, Katz J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain 2007;129:10-23
  8. Rheumatology Expert Group. Therapeutic guidelines: Principles of nonsteroidal anti-inflammatory drug use for musculoskeletal conditions in adults. West Melbourne: Therapeutic Guidelines Ltd, 2017 (accessed 29 January 2018).
  9. Rees D, Miles E, Banerjee T, et al. Dose-related effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men. Am J Clin Nutr 2006;83:331-42.
  10. Galarraga B, Ho M, Youssef H, et al. Cod liver oil (n-3 fatty acids) as an non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis. Rheumatology 2008;47:665-9.
  11. MacLean C, Mojica W, Morton S, et al. Effects of omega-3 fatty acids on lipids and glycemic control in type II diabetes and the metabolic syndrome and on inflammatory bowel disease, rheumatoid arthritis, renal disease, systemic lupus erythematosus, and osteoporosis. Evid Rep Technol Assess 2004;89:1-4.
  12. Cleland L, James M, Proudman S. Fish oil: what the prescriber needs to know. Arthritis Res Ther 2006;8:202.
  13. Proudman S, James M, Spargo L, et al. Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use. Ann Rheum Dis 2013;74:89-95.
  14. James M, Proudman S, Cleland L. Fish oil and rheumatoid arthritis: past, present and future. Proc Nutr Soc 2010;69:316-23.