Marine Oil Supplementation for Rheumatoid Arthritis
Research interest in omega-3 stems from its anti-inflammatory effects.
According to a report from the National Center for Health Statistics, fish oil is the most popular supplement taken by US adults.1 Fish oil contains omega-3, a group of essential polyunsaturated fatty acids (FAs) studied for everything from cardiovascular disease to cancer to diabetes to arthritis.2
In an interview with Rheumatology Advisor, Sara Tedeschi, MD, MPH, a rheumatologist at Harvard Medical School and Brigham and Women's Hospital in Boston, explained that research interest in omega-3 stems from its anti-inflammatory effects. "It has been recognized for decades that omega-3 [FAs] decrease the production of pro-inflammatory cytokines," she said.
Omega-3 FAs consist of 2 main types: long-chain and short-chain. Long-chain FAs include docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are derived from marine animals such as fish, seals, mussels, and krill. The primary short-chain omega-3 FA is alpha-linolenic acid, a plant-based FA derived from seeds, nuts, and vegetable oil, which Dr Tedeschi said is only "partially converted to EPA and DHA after ingestion." The body's inefficiency at converting alpha-linolenic acid is why omega-3 supplements typically use marine oil, a direct source of EPA and DHA.
Studies of Omega-3 Supplementation for Rheumatoid Arthritis Symptoms
Because rheumatoid arthritis (RA) is characterized by chronic inflammation, it is not surprising that researchers have long been interested in whether omega-3 supplements can improve RA symptoms. In a review article, Dr Tedeschi and associate Karen Costenbader, MD, MPH, also from Brigham and Women's Hospital, called omega-3 FAs "the most thoroughly studied potential dietary therapy for RA."3 Dr Tedeschi confirmed that "a number of clinical trials have studied omega-3 FA supplementation vs placebo in RA patients and demonstrated benefits, including decreased tender and swollen joint counts and less failure of concurrent triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine."
Other randomized trials of omega-3 supplementation in RA have reported reductions in the duration of morning stiffness, time to fatigue, and use of nonsteroidal anti-inflammatory drugs.4 In 2015, Proudman et al published results from a 1-year randomized controlled trial of high- vs low-dose fish oil supplementation in patients with newly diagnosed RA that associated higher levels of plasma phospholipid EPA and DHA with a significantly greater likelihood of achieving remission per American College of Rheumatology criteria (but not disease activity score of 28 joints [DAS28] remission).5
Recently, an international team of scientists from Denmark, the United States, and Canada conducted a systematic review and meta-analysis to quantify the effects of marine oil supplementation in arthritides.6 After an exhaustive literature search, they identified 42 randomized trials eligible for inclusion. The primary outcome was pain, and secondary outcomes were function and inflammation in patients with RA, osteoarthritis, or other types of arthritis.
The meta-analysis for pain in RA included 22 trials. Co-author Sabrina Mai Nielsen, MS, from the Parker Institute, Copenhagen University Hospital, Frederiksberg, Denmark, told Rheumatology Advisor that the research team found "moderate quality of evidence for our effect estimate on pain, indicating [marine oil had] a favorable effect in RA patients."6 She emphasized that the effect was small and that they could not say for certain whether it was clinically meaningful. In addition, whereas marine oil had no effect on function in patients with RA, it significantly improved inflammation.6 The authors cautioned that most trials they reviewed had serious limitations and possible biases, which Nielsen said undermined the team's confidence in the effect estimates.
Mechanism Behind Omega-3 FAs
A multitude of mechanisms has been proposed to explain how omega-3 FAs influence inflammation. One proposed mechanism is that DHA and EPA compete with an omega-6 FA known as arachidonic acid (AA) for enzymes that mediate cellular inflammation.6
Nielsen explained the complex process: "One theory is that DHA and EPA are homologues with AA and can be used in the same metabolism pathways involved in the regulation of inflammation. However, their end products — lipid mediators, such as eicosanoids, some of which mediate pain — are slightly different. Those produced from DHA and EPA are less potent compared with those produced from AA, which results in less inflammation and pain," she said. In other words, DHA and EPA are not reducing inflammation so much as causing less of it. Nielsen said consuming more DHA and EPA should allow more of the omega-3 FAs to enter the inflammatory pathway, thereby displacing AA.
Dr Tedeschi pointed out that researchers recently discovered another mechanism for the anti-inflammatory effects of omega-3 FAs. "[The omega-3] FAs give rise to a group of molecules called specialized pro-resolving mediators, which promote the cessation of inflammation," she said. These mediators, or resolvins, do not prevent inflammation but, instead, help shut off the process so that inflammation does not become chronic.7
Omega-3 Supplements and RA Prevention
Jill Norris, MPH, PhD, professor and chair of epidemiology at the Colorado School of Public Health in Aurora, and colleagues have been studying whether omega-3 FAs might have a protective effect against RA.8 Their studies have found that people with anti-cyclic citrullinated peptide, an RA-related autoantibody associated with increased risk for RA, had lower circulating levels of EPA and DHA in their blood than people without anti-cyclic citrullinated peptide autoantibodies. "Our results are exciting, as they imply that omega-3 FAs such as EPA and DHA could be used to help prevent the development of autoimmunity, which in turn could prevent the development of RA," Dr Norris said in an interview. "Furthermore, our results suggest that omega-3 FAs and their corresponding lipid derivatives could have a greater impact on the regulation of the adaptive immune system than previously thought," she added.
Dr Norris cautioned that "more scientific research is needed to draw any definitive conclusions on the utility of omega-3 FA at preventing RA." She and her colleagues plan to continue following their current cohort to see whether omega-3 FAs influence whether a person with anti-cyclic citrullinated peptide autoantibodies progresses to RA.
Recommending Fish Oil Supplements to Patients With RA
Studies have not sufficiently established that omega-3 supplements relieve RA symptoms for omega-3 supplementation to become standard care. Nielsen noted, "At least one rigorous, well-designed, conducted and reported randomized controlled trial would be preferable to confirm the benefit in RA." She said the trials they reviewed did not show any harmful effects from marine oil supplementation, so it might be worth trying for some patients. However, Nielsen and colleagues found that heterogeneity between study protocols made it impossible to recommend an optimal dose, duration of treatment, or type of marine oil to use. She advised that future trials should endeavor to answer those questions.
The Academy of Nutrition and Dietetics recommends healthy adults obtain omega-3 FAs from food before turning to supplements.9 Dr Tedeschi said the question of whether patients with RA should rely on food or supplements as a source for DHA and EPA has not been well-studied. She implied that it cannot be assumed findings from a study of omega-3 FA supplementation in RA would be identical to findings from a study investigating increased consumption of foods containing omega-3 FAs.
"Omega-3 FAs consumed in the context of proteins, other fats, and other nutrients contained in fish may have a different biological effect on RA disease activity due to interactions with these other macro- and micronutrients," she advised. Dr Tedeschi, however, did relay that her group is currently investigating the relationship between fish consumption and RA disease activity.
- Clarke TC, Black LI, Stussman BJ, Barnes PM, Nahin RL. National health statistics reports; no. 79. Hyattsville, MD: National Center for Health Statistics. 2015.
- National Center for Complementary and Integrative Health. Omega-3 supplements: in depth. https://nccih.nih.gov/health/omega3/introduction.htm. Updated August 2015. Accessed February 10.
- Tedeschi S, Costenbader KH. Is there a role for diet in the therapy of rheumatoid arthritis? Curr Rheumatol Rep. 2016;18:23. doi: 10.1007/s11926-016-0575-y
- Miles EA, Calder PC. Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis. Br J Nutr. 2012;107(suppl2):S171-S184. doi: 10.1017/S0007114512001560
- Proudman SM, Cleland LG, Metcalf RG, Sullivan TR, Spargo LD, James MJ. Plasma n-3 fatty acids and clinical outcomes in recent-onset rheumatoid arthritis. Br J Nutr. 2015;114:885-890. doi: 10.1017/S0007114515002718
- Senftleber NK, Nielsen SM, Andersen JR, et al. Marine oil supplements for arthritis pain: a systematic review and meta-analysis of randomized trials. Nutrients. 2017;9:42. doi: 10.3390/nu9010042
- Calder PC. Omega-3 fatty acids and inflammatory processes. Nutrients. 2010;2:355-374. doi: 10.3390/nu2030355
- Gan RW, Demoruelle MK, Deane KD, et al. Omega-3 fatty acids are associated with a lower prevalence of autoantibodies in shared epitope-positive subjects at risk for rheumatoid arthritis. Ann Rheum Dis. 2017;76:147-152. doi: 10.1136/annrheumdis-2016-209154
- Vannice G, Rasmussen H. Position of the Academy of Nutrition and Dietetics: dietary fatty acids for healthy adults. J Acad Nutr Diet. 2014;114:136-153. doi: 10.1016/j.jand.2013.11.001