Skip to main content Accessibility help
×
Home

Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis

Published online by Cambridge University Press:  17 May 2012

Elizabeth A. Miles
Affiliation:
Institute of Human Nutrition and Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, IDS Building, MP887 Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK
Philip C. Calder
Affiliation:
Institute of Human Nutrition and Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, IDS Building, MP887 Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK
Corresponding
E-mail address:
Rights & Permissions[Opens in a new window]

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of the joints and bones. The n-6 polyunsaturated fatty acid (PUFA) arachidonic acid (ARA) is the precursor of inflammatory eicosanoids which are involved in RA. Some therapies used in RA target ARA metabolism. Marine n-3 PUFAs (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) found in oily fish and fish oils decrease the ARA content of cells involved in immune responses and decrease the production of inflammatory eicosanoids from ARA. EPA gives rise to eicosanoid mediators that are less inflammatory than those produced from ARA and both EPA and DHA give rise to resolvins that are anti-inflammatory and inflammation resolving, although little is known about these latter mediators in RA. Marine n-3 PUFAs can affect other aspects of immunity and inflammation relevant to RA, including dendritic cell and T cell function and production of inflammatory cytokines and reactive oxygen species, although findings for these outcomes are not consistent. Fish oil has been shown to slow the development of arthritis in animal models and to reduce disease severity. A number of randomised controlled trials of marine n-3 PUFAs have been performed in patients with RA. A systematic review included 23 studies. Evidence is seen for a fairly consistent, but modest, benefit of marine n-3 PUFAs on joint swelling and pain, duration of morning stiffness, global assessments of pain and disease activity, and use of non-steroidal anti-inflammatory drugs.

Type
Full Papers
Copyright
Copyright © The Authors 2012

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of the joints and bones(Reference Firestein1). Joint inflammation is manifested by swelling, pain, functional impairment, morning stiffness, osteoporosis, and muscle wasting. Bone erosion commonly occurs in the joints of the hands and feet. The joint lesions are characterised by infiltration of immune cells and contain high concentrations of many of the chemical mediators they produce(Reference Feldmann and Maini2). One pharmaceutical treatment for the inflammation involved in RA has involved the use of non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs target the metabolism of the n-6 fatty acid arachidonic acid (ARA) to prostaglandins (PGs) by cyclooxygenase (COX) enzymes, suggesting a key involvement of these mediators in the pathology of RA. N-3 fatty acids from oily fish and fish oils target ARA availability and metabolism and also influence several other immuno-inflammatory responses involved in RA. Thus, marine n-3 fatty acids could be useful in treating RA. This article will describe the effects of marine n-3 fatty acids on different aspects of immune responses of relevance to RA, and will then describe the effects of marine n-3 fatty acids in animal models of RA. The article will then report on a systematic evaluation of marine n-3 fatty acids in clinical trials with RA patients. Finally, the findings of the systematic evaluation will be compared with the conclusions of meta-analyses of the efficacy of marine n-3 fatty acids in RA. Parts of this article are updated from an earlier one on this topic(Reference Calder3).

Rheumatoid arthritis

RA is a chronic inflammatory autoimmune disease that affects about 1 % of adults. It is more common in women than in men. The joint lesions show infiltration of activated T lymphocytes, macrophages and antibody-secreting B lymphocytes into the synovium (the tissue lining the joints) and there is proliferation of fibroblast-like synovial cells called synoviocytes(Reference Sweeney and Firestein4). These cells and new blood vessels form a tissue termed pannus which leads to progressive destruction of cartilage and bone. This is most likely due to cytokine- and eicosanoid-mediated induction of destructive enzymes such as matrix metalloproteinases. Synovial fluid from patients with RA contains high levels of pro-inflammatory cytokines including tumour necrosis factor (TNF)-α, IL-1β, IL-6, IL-8 and granulocyte/macrophage colony stimulating factor(Reference Feldmann and Maini2). Synovial cells cultured ex vivo spontaneously produce these cytokines for extended periods of time(Reference Feldmann and Maini2). RA is also characterised by signs of systemic inflammation, such as elevated plasma concentrations of some cytokines (e.g. interleukin (IL)-6), acute phase proteins, and rheumatoid factors.

Genetic studies have linked susceptibility to, and severity of, RA to genes in the major histocompatibility class (MHC) II locus(Reference Bowes and Barton5); in humans these genes encode the human leukocyte antigen (HLA) II proteins involved in antigen presentation. RA is associated with specific alleles of the HLA-DRB1 gene, although other HLA-DR alleles may also play a role(Reference Bowes and Barton5). Because the function of HLA-DR is antigen presentation to T lymphocytes, the genetic association indicates a role for T cells in RA(Reference Panayi6). In total, the HLA region contributes 30 to 50 % of the genetic component of RA. The second largest genetic risk for RA lies with a variant in the protein tyrosine phosphatse non-receptor 22 gene, which encodes an intracellular protein tyrosine phosphatase(Reference Bowes and Barton5). The variant may act to reduce the ability to down-regulate activated T cells.

Arachidonic acid, eicosanoids and the links with inflammation and RA

Eicosanoids are amongst the most important mediators and regulators of inflammation(Reference Tilley, Coffman and Koller7). They are formed from 20 carbon polyunsaturated fatty acids (PUFAs). Because immune cells usually contain a high proportion of the n-6 PUFA ARA and low proportions of other 20-carbon PUFAs, ARA is considered to be the major substrate for synthesis of eicosanoids. Eicosanoids include PGs, thromboxanes, leukotrienes (LTs) and other oxidised derivatives. Fig. 1 summarises the pathway of synthesis of these mediators from ARA(Reference Calder8). COX is key to synthesis of PGs and there are two principal COX isoforms. These are COX-1, which is constitutively expressed, and COX-2, which is up-regulated by inflammatory stimuli. Expression of both COX isoforms is increased in the synovium of patients with RA and in joint tissues in rat models of arthritis(Reference Sano, Hla and Maier9). Eicosanoids produced by both the COX and lipoxygenase (LOX) pathways are found in the synovial fluid of patients with active RA(Reference Sperling10). Infiltrating leukocytes such as neutrophils, monocytes and synoviocytes are the key sources of eicosanoids in RA(Reference Sperling10). PGE2 has a number of proinflammatory effects including increasing vascular permeability, vasodilation, blood flow and local pyrexia, and potentiating pain caused by other agents. It also promotes the production of some of the destructive matrix metalloproteinases and stimulates bone resorption. The efficacy of NSAIDs, which are COX inhibitors, in RA indicates the importance of this pathway in the pathophysiology of the disease. These drugs provide rapid relief of pain and stiffness by inhibiting joint inflammation. LTB4 increases vascular permeability, enhances local blood flow, is a potent chemotactic agent for leukocytes, induces release of lysosomal enzymes, and enhances release of reactive oxygen species and inflammatory cytokines like TNF-α, IL-1β and IL-6.

Fig. 1 Outline of the pathway of eicosanoid synthesis from arachidonic acid. COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; LOX, lipoxygenase; LT, leukotriene; PG, prostaglandin; TX, thromboxane. Taken from Calder(Reference Calder8) with permission.

Fatty acid modification of immune cell fatty acid composition and of eicosanoid profiles

Fatty acids are constituents of phospholipids and phospholipids are components of cell membranes. The bulk phospholipids of immune cells (e.g. neutrophils, lymphocytes, monocytes) isolated from the blood of healthy people consuming typical Western diets have been reported to contain about 10 to 20 % of fatty acids as ARA, with about 0·5-1 % of the n-3 PUFA eicosapentaenoic acid (EPA) and about 1·5-3 % of another n-3 PUFA docosahexaenoic acid (DHA)(Reference Lee, Hoover and Williams11Reference Healy, Wallace, Miles, Calder and Newsholme17). There are, however, differences between the different phospholipid classes in terms of the content of these fatty acids(Reference Sperling, Benincaso and Knoell13). EPA and DHA are found in seafood, especially oily fish, and in fish oil-type supplements. Thus EPA and DHA may be referred to as marine n-3 PUFAs. The fatty acid composition of human blood leukocytes can be modified by increasing the oral intake of marine n-3 PUFAs. This results in increased proportions of EPA and DHA in blood monocytes, mononuclear cells and neutrophils(Reference Lee, Hoover and Williams11Reference Rees, Miles and Banerjee21). Typically the increase in content of marine n-3 PUFAs occurs at the expense of n-6 PUFAs, including ARA. Time-course studies suggest that the incorporation of EPA and DHA into human blood leukocytes begins within days and reaches its peak within one or two weeks of commencing increased intake(Reference Yaqoob, Pala, Cortina-Borja, Newsholme and Calder16Reference Thies, Nebe-von-Caron and Powell18, Reference Kew, Mesa and Tricon20Reference Faber, Berkhout and Vos22). Studies using multiple doses of fish oil show that the incorporation of EPA and DHA into human blood leukocytes occurs in a dose-response manner(Reference Healy, Wallace, Miles, Calder and Newsholme17, Reference Rees, Miles and Banerjee21, Reference Calder23).

There are many reports of decreased production of PGE2 and of 4 series-LTs by immune cells following a period of fish oil supplementation of the diet of healthy volunteers(Reference Lee, Hoover and Williams11Reference Sperling, Benincaso and Knoell13, Reference Caughey, Mantzioris, Gibson, Cleland and James15, Reference Meydani, Endres and Woods24, Reference Von Schacky, Kiefl, Jendraschak and Kaminski25). Similar effects are seen in patients with RA, where fish oil supplements decreased LTB4 production by neutrophils(Reference Kremer, Bigauoette and Michalek26Reference van der Tempel, Tullekan, Limburg, Muskiet and van Rijswijk31) and monocytes(Reference Cleland, French, Betts, Murphy and Elliot30), 5-hydroxyeicosatetraenoic acid production by neutrophils(Reference Cleland, French, Betts, Murphy and Elliot30), and PGE2 production by mononuclear cells(Reference Cleland, Caughey, James and Proudman32).

The studies in humans demonstrating a reduction in ARA-derived eicosanoid production by oral marine n-3 fatty acids have typically used fairly high intakes (several g/day). A dose-response study in healthy volunteers reported that an EPA intake of 1·35 g/d for 3 months was not sufficient to influence ex vivo PGE2 production by endotoxin stimulated mononuclear cells, whereas an EPA intake of 2·7 g/day significantly decreased PGE2 production(Reference Rees, Miles and Banerjee21). These data suggest a threshold of intake of EPA to elicit an anti-inflammatory effect; this threshold would be between 1·35 and 2·7 g/day.

EPA is also a substrate for the COX and LOX enzymes that produce eicosanoids (Fig. 2), but the mediators formed have a different structure from the ARA-derived mediators. Neutrophils from healthy volunteers supplemented orally with fish oil for several weeks produced much increased amounts of 5-series LTs(Reference Lee, Hoover and Williams11Reference Sperling, Benincaso and Knoell13). In patients with RA given marine n-3 PUFAs, there was generation of the usually undetectable LTB5 and 5-hydroxyeicosapentaenoic acid by stimulated neutrophils(Reference Sperling, Weinblatt and Robin29Reference van der Tempel, Tullekan, Limburg, Muskiet and van Rijswijk31) and monocytes(Reference Sperling, Weinblatt and Robin29). The functional significance of generation of eicosanoids from EPA is that EPA-derived mediators are often much less biologically active than those produced from ARA(Reference Goldman, Pickett and Goetzl33Reference Bagga, Wang, Farias-Eisner, Glaspy and Reddy35) and they may even act as antagonists of the ARA-derived mediators(Reference Tull, Yates and Maskrey36).

Fig. 2 Overview of eicosanoid and resolvin synthesis from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Abbreviations used: LT, leukotriene; PG, prostaglandin.

Resolvins: Novel anti-inflammatory and inflammation resolving mediators produced from EPA and DHA

EPA and DHA both give rise to a family of lipid mediators termed resolvins (Fig. 2). The pathways of synthesis of resolvins are complex and not fully elucidated yet, but they involve the action of both COX and LOX enzymes and may be modified in the presence of aspirin. E-series resolvins are produced from EPA and D-series resolvins from DHA. DHA is also a substrate for similar molecules called protectins, also known as neuroprotectins. A large number of studies using cell culture and animal models have convincingly shown that E- and D-series resolvins and protectins are anti-inflammatory, inflammation resolving and immunomodulatory(Reference Serhan, Clish and Brannon37Reference Marcheselli, Hong, Lukiw and Hua Tian41). There is very limited human data on resolvins and they have not yet been studied in the context of RA.

Influence of marine n-3 fatty acids on production of inflammatory cytokines

Cell culture studies report that EPA and DHA can inhibit the production of the classic pro-inflammatory cytokines (TNF-α, IL-1, IL-6) by several cell types(Reference De Caterina, Cybulsky, Clinton, Gimbrone and Libby42Reference Zhao, Joshi-Barve, Barve, Chen, Barve and Chen47), effects supported by animal feeding studies(Reference Calder8). Several studies in healthy human volunteers involving supplementation of the diet with fish oil have demonstrated decreased production of TNF-α, IL-1β and IL-6 by endotoxin-stimulated monocytes or mononuclear cells (a mixture of lymphocytes and monocytes)(Reference Endres, Ghorbani and Kelley12, Reference Caughey, Mantzioris, Gibson, Cleland and James15, Reference Meydani, Endres and Woods24, Reference Trebble, Arden and Stroud48Reference Gallai, Sarchielli and Trequattrini52), although not all studies confirm this effect(Reference Yaqoob, Pala, Cortina-Borja, Newsholme and Calder16, Reference Kew, Mesa and Tricon20, Reference Rees, Miles and Banerjee21, Reference Thies, Miles and Nebe-von-Caron53Reference Cannon, Fiatarone and Meydani58). Reasons for the different findings include the low n-3 PUFA dose, the short duration and the small sample size of some of the studies failing to find an effect, but these are unlikely to be the sole explanations. Studies using fish oil in patients with RA report decreased IL-1 production by monocytes(Reference Kremer, Lawrence and Jubiz28), and decreased circulating concentrations of IL-1β(Reference Esperson, Grunnet and Lervang59, Reference Kremer, Lawrence and Petrillo60), TNF-α(Reference Adam, Beringer and Kless61, Reference Kolahi, Ghorbanihaghjo and Alizadeh62) and soluble receptor activator of nuclear factor kappa B ligand(Reference Kolahi, Ghorbanihaghjo and Alizadeh62).

Influence of marine n-3 fatty acids on production of reactive oxygen species

Providing high doses (>3 g/day) of marine n-3 PUFAs to healthy volunteers resulted in decreased production of reactive oxygen species (superoxide or hydrogen peroxide) by blood neutrophils stimulated with different agents(Reference Varming, Schmidt and Svaneborg63Reference Luostarinen and Saldeen65) and high dose marine n-3 PUFAs decreased hydrogen peroxide production by human monocytes(Reference Fisher, Levine and Weiner66). Studies using lower doses of marine n-3 PUFAs ( <  2·3 g/day) did not see effects on reactive oxygen species production by either neutrophils or monocytes(Reference Healy, Wallace, Miles, Calder and Newsholme17, Reference Thies, Miles and Nebe-von-Caron53Reference Miles, Banerjee, Dooper, M'Rabet, Graus and Calder55, Reference Schmidt, Varming, Moller, Bulow Pederson, Madsen and Dyerberg67). Rees et al. (Reference Rees, Miles and Banerjee21) identified an EPA dose-dependent decrease in the number of blood neutrophils producing superoxide in elderly subjects, but there was no effect in younger subjects. Fish oil supplements decreased reactive oxygen species production by neutrophils from the blood of RA patients(Reference Magaro, Altomonte and Zoli68).

Influence of marine n-3 fatty acids on T cells

Cell culture studies report that EPA and DHA inhibit proliferation of human T cells and their production of IL-2(Reference Calder and Newsholme69). Animal feeding studies support these observations(Reference Calder8), but human data in this area are inconsistent. Some studies in healthy humans report that increased intake of marine n-3 PUFAs decreases human T cell proliferation(Reference Thies, Nebe-von-Caron and Powell18, Reference Meydani, Endres and Woods24, Reference Molvig, Pociot and Worsaae57) and IL-2 production(Reference Meydani, Endres and Woods24, Reference Gallai, Sarchielli and Trequattrini52), but several other studies show no effect on these outcomes(Reference Yaqoob, Pala, Cortina-Borja, Newsholme and Calder16, Reference Trebble, Arden and Stroud48, Reference Wallace, Miles and Calder49, Reference Kew, Banerjee and Minihane54, Reference Miles, Banerjee, Dooper, M'Rabet, Graus and Calder55, Reference Miles, Banerjee, Wells and Calder70). Again the reasons for these different findings may include the low n-3 PUFA dose, the short duration and the small sample size of some of the studies; differences in the age of the subjects studied might also contribute to the variation in findings(Reference Meydani, Endres and Woods24).

Influence of marine n-3 fatty acids on antigen presentation

A small number of cell culture studies have found that MHC II expression and antigen presentation via MHC II are decreased following exposure of antigen presenting cells to EPA or DHA(Reference Khair-El-Din, Sicher, Vazquez, Wright and Lu71, Reference Hughes, Southon and Pinder72). These findings are supported by work in animals fed fish oil(Reference Calder73), but there is limited information on n-3 PUFAs and antigen presentation in humans(Reference Hughes, Pinder, Piper, Johnson and Lund74).

Marine n-3 PUFAs and animal models of RA

The effects of marine n-3 PUFAs on antigen presentation, T cell reactivity, and inflammatory lipid, peptide and oxygen-derived mediator production suggest that these fatty acids might have a role both in decreasing the risk of development of RA and in decreasing severity in those patients with the disease. This has been explored using animal models of arthritis. In an early study, compared with vegetable oil, fish oil fed mice had delayed onset (mean 34 days vs. 25 days) and reduced incidence (69 % vs. 93 %) and severity (mean peak severity score 6·7 vs. 9·8) of type II collagen-induced arthritis(Reference Leslie, Gonnerman and Ullman75). In another study, both EPA and DHA suppressed Streptococcal cell wall-induced arthritis in rats, although EPA was more effective(Reference Volker, FitzGerald and Garg76). A recent study compared fish oil, which provides marine n-3 PUFAs in triglyceride form, and krill oil, which provides marine n-3 PUFAs partly in the form of phospholipids, in collagen-induced arthritis in the susceptible DBA/1 mouse strain(Reference Ierna, Kerr, Scales, Berge and Griinari77). Both chemical formulations of marine n-3 PUFAs slowed the onset of arthritis, decreased its severity, reduced paw swelling, and decreased knee joint pathology compared with the control group; for some outcomes krill oil appeared superior to fish oil.

A systematic review of randomized controlled trials of orally administered marine n-3 PUFAs in RA

Introduction

The studies outlined above indicate that oral marine n-3 PUFAs can modulate a range of immunological reactions that are associated with the immunological dysfunction or inflammation-induced pathology associated with RA; aspects reported to be modified by marine n-3 PUFAs in some studies in healthy volunteers or in RA patients include antigen presentation, T cell reactivity, reactive oxygen species production by leukocytes, inflammatory cytokine production by macrophages, and inflammatory eicosanoid production by various cells. These effects have been demonstrated mainly in healthy volunteers, but similar findings are made in a small number of studies in patients with RA(Reference Kremer, Bigauoette and Michalek26Reference Cleland, Caughey, James and Proudman32, Reference Esperson, Grunnet and Lervang59Reference Kolahi, Ghorbanihaghjo and Alizadeh62, Reference Magaro, Altomonte and Zoli68). Animal models of arthritis have been used to demonstrate a benefit from marine n-3 PUFAs(Reference Leslie, Gonnerman and Ullman75Reference Ierna, Kerr, Scales, Berge and Griinari77). These observations, particularly the early finding that marine n-3 PUFAs decrease eicosanoid formation from ARA, have lead to a number of clinical trials of oral marine n-3 PUFAs, usually in the form of fish oil, in patients with RA. The rest of this article is given over to as systematic review of randomized, controlled trials of oral marine n-3 PUFAs in adults with RA.

Identification of articles to include in the systematic review

A PubMed search was performed on 25 November 2011 using the MeSH terms (Fatty acids, Omega-3 OR Fish oils) AND Arthritis, Rheumatoid AND Human. The search identified 155 articles. The a priori inclusion criteria for the systematic review were:

  • randomized, controlled trial

  • use of marine n-3 PUFAs

  • oral administration through supplements or foods

  • published in full as a research paper

  • published in English

  • reporting clinical outcomes

Examination of the titles and short PubMed descriptions of the articles resulted in exclusion of 80 review, discussion, opinion, and comment articles, of two meta-analyses, of 16 articles not written in English, of four articles in which n-3 PUFAs were administered by a non-oral route (e.g. intravenously), and of two articles not about n-3 PUFAs (Fig. 3). The abstracts of the remaining 51 articles were read. This lead to exclusion of a further 28 articles (Fig. 3). The full text of the remaining 23 articles was read; based on this two articles were excluded (Fig. 3). Reference lists in three meta-analyses(Reference Fortin, Lew and Liang78Reference Goldberg and Katz80) were read to identify further relevant studies; two were included after reading their full text. Thus, the systematic review included 23 articles (Fig. 3). Studies of plant n-3 PUFAs are not included.

Fig. 3 Overview of the selection of articles for inclusion in the systematic review.

Description of the included studies

Table 1 describes the studies included in the systematic review including aspects of study design, sample size, dose of EPA plus DHA used, duration, nature of the placebo, JADAD score(Reference Jadad, Moore and Carroll81) and whether the study was included in a previous meta-analysis of n-3 PUFAs and RA. Included studies were published between 1985 and 2009(Reference Kremer, Bigauoette and Michalek26Reference Kremer, Lawrence and Jubiz28, Reference Cleland, French, Betts, Murphy and Elliot30, Reference van der Tempel, Tullekan, Limburg, Muskiet and van Rijswijk31, Reference Kremer, Lawrence and Petrillo60, Reference Adam, Beringer and Kless61, Reference Magaro, Altomonte and Zoli68, Reference Belch, Ansell, Madhok, O'Dowd and Sturrock82Reference Das Gupta, Hossain, Islam, Dey and Khan95). Most studies adopted a parallel design, although four adopted a random order, cross-over design. This latter design is not optimal for studying effects of marine n-3 PUFAs because of their slow turnover which requires a significant wash-out phase. Wash-out periods of 4, 4 and 8 weeks were used in three of the studies employing this design; there was no wash-out phase in a fourth study of this type. Sample size was typically modest and only four studies appear to have included a formal power calculation(Reference van der Tempel, Tullekan, Limburg, Muskiet and van Rijswijk31, Reference Adam, Beringer and Kless61, Reference Skoldstam, Borjesson, Kjallman, Seiving and Akesson84, Reference Remans, Sont and Wagenaar90). Most articles did not mention a specific primary outcome. The dose of EPA plus DHA used in these studies varied from < 1 to >7 g/day and averaged about 3 g/day; one study did not specify intake of either EPA or DHA(Reference Das Gupta, Hossain, Islam, Dey and Khan95). Twenty-one of the studies provided marine n-3 PUFAs as fish oil type supplements. One study used a liquid formula containing EPA plus DHA in addition to other nutrients(Reference Remans, Sont and Wagenaar90), while one used modified foods containing marine n-3 PUFAs(Reference Dawczynski, Schubert and Hein94). Two studies(Reference Kremer, Lawrence and Jubiz28, Reference Geusens, Wouters, Nijs, Jiang and Dequeker88) evaluated two doses of marine n-3 PUFAs. Duration of the included studies varied from 4 to 52 weeks; some studies reported data at several intermediate time points. The placebo used in the studies was highly variable and commonly included another “nutritional” oil (e.g. coconut, olive or corn oil) or a mixture of such oils. In some cases the inert oil paraffin oil was used. The JADAD score(Reference Jadad, Moore and Carroll81) of the included studies was typically 3, although some studies scored lower than this. None of the included studies provided information about how patients were randomised or how the blinding was performed. For some studies it seems unlikely that patients were blind to their treatment. For example in the studies by Magaro et al. (Reference Magaro, Altomonte and Zoli68) and Das Gupta et al. (Reference Das Gupta, Hossain, Islam, Dey and Khan95), the control group did not receive any placebo supplement. Most studies provided relevant information about drop-outs and withdrawals. Statistical analysis of the results of most of the studies was poor, often relying upon multiple pairwise comparisons with no correction. The designs of many of the studies would merit a more sophisticated analytical approach than was used; for example for many of the studies a two-factor analysis of variance (factors: time and treatment) with appropriate covariates would have been appropriate. In many cases the focus of the analysis was on comparison to baseline within a group, rather than on comparison between the treatment and control group. This restricts the interpretation of some of the findings.

Table 1 Summary of the studies included in the systematic review of marine n-3 PUFAs and clinical outcomes in rheumatoid arthritis

A range of clinical outcomes was reported in the included studies (Table 2). The most commonly reported outcomes were related to tender or swollen joints, duration of morning stiffness, grip strength, physician or patient assessment of pain or disease severity, and use of NSAIDs. All studies reported multiple clinical outcomes (Table 2).

Table 2 Clinical outcomes assessed in the studies included in the systematic review of marine n-3 PUFAs in rheumatoid arthritis

Findings of the included studies

Almost all of the trials included here showed some clinical benefit of marine n-3 PUFAs (Table 3). Commonly reported benefits include reduced duration of morning stiffness, reduced number of tender or swollen joints, reduced joint pain, reduced time to fatigue, increased grip strength, reduced pain or disease activity (assessed by physician or patient) and decreased use of NSAIDs (Table 3). These effects are frequently reported within the n-3 PUFA group comparing back to the baseline value. Much less frequent benefits are reported compared with the placebo group (Table 3). Kremer et al. (Reference Kremer, Lawrence and Jubiz28) reported that both a “low” and a “high” dose of marine n-3 PUFAs brought about a similar clinical benefit, but that the effect of the high dose became apparent (i.e. significant) sooner. An interesting approach was used in the study of Adam et al. (Reference Adam, Beringer and Kless61) where marine n-3 PUFAs or placebo were given against a background of a Western diet or a so-called anti-inflammatory diet. The latter aimed to reduce the intake of n-6 PUFAs, especially ARA, on the basis that the effects of marine n-3 PUFAs might be stronger if n-6 PUFA intake (and status) was decreased simultaneously with the increased n-3 PUFA intake. Indeed n-3 PUFAs had benefits irrespective of background diet, but the effect was greater when intake of ARA was decreased. Three studies used fairly low intakes ( <  1·5 g EPA+DHA/day) of marine n-3 PUFAs(Reference Belch, Ansell, Madhok, O'Dowd and Sturrock82, Reference Remans, Sont and Wagenaar90, Reference Dawczynski, Schubert and Hein94), which may explain why those studies are the only ones that fail to report any clinical benefit from marine n-3 PUFAs. Using LPS-stimulated PGE2 production from blood mononuclear cells as a model, Rees et al. (Reference Rees, Miles and Banerjee21) identified an “anti-inflammatory threshold” for EPA intake in healthy volunteers of between 1·35 and 2·7 g/day.

Table 3 Summary of the findings of randomised, controlled studies using marine n-3 PUFAs in patients with rheumatoid arthritis

Comparison between the findings of the systematic review and the conclusions of previous meta-analyses

Table 4 summarizes the findings by indicating the number of studies that demonstrated a significant benefit (either vs. baseline or vs. placebo, the latter being more important) for the commonly reported outcomes. This organization of the outcomes emphasizes the lack of consistent findings across all of the studies conducted, but also shows the fairly high number of studies that have demonstrated a given clinical benefit. The most likely reasons for lack of consistency of findings relate to the dose of EPA+DHA used, which is probably too low in some of the studies; the small sample size of many of the studies, which in many cases has probably limited the ability to identify an effect; and the sub-optimal approaches to statistical analysis used in many of the studies. Overall it seems that marine n-3 PUFAs do reduce join pain and swelling, decrease the duration of morning stiffness, and spare the need for some anti-inflammatory medications.

Table 4 Summary of findings of this systematic review and comparison with the findings of previous meta-analyses(Reference Fortin, Lew and Liang78Reference Goldberg and Katz80)

These conclusions can be compared with those of three meta-analyses(Reference Fortin, Lew and Liang78Reference Goldberg and Katz80). The meta-analysis of Fortin et al. (Reference Fortin, Lew and Liang78) included data from nine trials published between 1985 and 1992 inclusive and from one unpublished trial; 8 of the published trials are included in the current systematic review (Table 1). Fortin et al. concluded that “dietary fish oil supplementation for three months significantly reduces tender joint count (mean difference − 2·9; P = 0·001) and morning stiffness (mean difference − 25·9 minutes; − = 0·01)”. Maclean et al. (Reference MacLean, Mojica and Morton79) conducted a meta-analysis that included data from trials published between 1985 and 2002, although these included one study of flaxseed oil, one study that did not use a control for fish oil, and one study in which transdermal administration of n-3 PUFAs by ultrasound, rather than the oral route, was used. Maclean et al. concluded that fish oil supplementation has no effect on “patient report of pain, swollen joint count, disease activity, or patient's global assessment”. However, this conclusion may be flawed, because of the inappropriate manner in which studies were combined and because of a poor understanding of the study designs used. For example, the meta-analysis fails to recognize that patients' ability to reduce the need for using NSAIDs or their ability to be withdrawn from NSAID use, as was done in some designs, must indicate a reduction in pain with n-3 PUFA use. This meta-analysis does state that “in a qualitative analysis of seven studies that assessed the effect of n-3 fatty acids on anti-inflammatory drug or corticosteroid requirement, six demonstrated reduced requirement for these drugs” and concluded that “n-3 fatty acids may reduce requirements for corticosteroids”. The effect of marine n-3 PUFAs on tender joint count was not assessed by Maclean et al., who simply reiterated the findings of Fortin et al. that “n-3 fatty acids reduce tender joint counts”. Goldberg and Katz(Reference Goldberg and Katz80) published a meta-analysis of 17 trials of n-3 PUFAs in the context of joint pain, including one trial in RA with flaxseed oil and two trials of fish oil not in RA patients. Data on six outcomes were analysed. This analysis indicated that fish oil reduces patient assessed joint pain (n 13 studies; 26 % reduction; P = 0·03), duration of morning stiffness (n 8 studies; 57 % reduction; P = 0·003), number of painful and/or tender joints (n 10 studies; 71 % reduction; P = 0·003), and consumption of NSAIDs (n 3 studies; 60 % reduction; P = 0·01). However, this meta-analysis also found that there was no effect of marine n-3 PUFAs on Ritchie's articular index (n 4 studies) or on patient assessed disease activity (n 5 studies). Nevertheless, the meta-analysis of Goldberg and Katz provides good evidence for the clinical efficacy of n-3 PUFAs in RA, and the conclusions of the current systematic review are similar.

Overall conclusions

Eicosanoids derived from the n-6 PUFA ARA play a role in RA, and the efficacy of NSAIDs in RA indicates the importance of pro-inflammatory COX pathway products in the pathophysiology of the disease. At sufficiently high intakes, marine n-3 PUFAs decrease the production of inflammatory eicosanoids from ARA and promote the production of less inflammatory eicosanoids from EPA and of anti-inflammatory resolvins and related mediators from EPA and DHA. Marine n-3 PUFAs have other anti-inflammatory actions including decreasing antigen presentation via MHC II, decreasing T cell reactivity and Th1-type cytokine production, decreasing inflammatory cytokine production by monocyte/macrophages, and decreasing reactive oxygen species production by various leukocytes, although these effects are not consistently reported. One reason behind the lack of consistency may be the dose of EPA plus DHA used in many studies which was probably below the “anti-inflammatory threshold”. Other contributors would include differences in duration of the intervention, in sample size, and in the age of the subjects studied. Work with animal models of RA has demonstrated efficacy of fish oil. There have been a number of clinical trials of fish oil in patients with RA. Most of these trials report some clinical improvements (e.g. improved patient assessed pain, decreased morning stiffness, fewer painful or tender joints, decreased use of NSAIDs), and when the trials have been pooled in meta-analyses statistically significant clinical benefit has emerged. The current systematic review supports the conclusion that there is fairly consistent evidence for a modest clinical efficacy of marine n-3 PUFAs in RA.

Acknowledgements

There was no funding associated with the writing of this article.

Authors' contributions:

PCC conducted the literature search; both authors scored, interpreted and discussed the clinical trials; PCC drafted the article; both authors agreed the final version of the article. Conflicts of interest:

PCC serves on Scientific Advisory Boards of the Danone Research Centre in Specialised Nutrition and Aker Biomarine. He acts as a consultant to Mead Johnson Nutritionals, Vifor Pharma, and Amarin Corporation. He has received speaking honoraria from Solvay Healthcare, Solvay Pharmaceuticals, Pronova Biocare, Fresenius Kabi, B. Braun, Abbott Nutrition, Baxter Healthcare, Nestle, Unilever and DSM. He currently receives research funding from Vifor Pharma. He is elected President of the International Society for the Study of Fatty Acids and Lipids, an organisation that is partly supported by corporate membership fees, mainly the food and supplements industries. He is a member of the Board of Directors of ILSI Europe, the Board of Directors of the European Neutraceutical Association, and the Council of the British Nutrition Foundation; these organizations are each supported in part by the food and supplements industries. EAM has no conflicts of interest.

References

1 Firestein, GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423, 356361.Google Scholar
2 Feldmann, M & Maini, RN (1999) The role of cytokines in the pathogenesis of rheumatoid arthritis. Rheumatol 38, Suppl. 2, 37.Google Scholar
3 Calder, PC (2008) PUFA, inflammatory processes and rheumatoid arthritis. Proc Nutr Soc 67, 409418.Google Scholar
4 Sweeney, SE & Firestein, GS (2004) Rheumatoid arthritis: regulation of synovial inflammation. Int J Biochem Cell Biol 36, 372378.Google Scholar
5 Bowes, J & Barton, A (2008) Recent advances in the genetics of RA susceptibility. Rheumatol 47, 399402.Google Scholar
6 Panayi, GS (1999) Targetting of cells involved in the pathogenesis of rheumatoid arthritis. Rheumatol 38, Suppl. 2, 810.Google Scholar
7 Tilley, SL, Coffman, TM & Koller, BH (2001) Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes. J Clin Invest 108, 1523.Google Scholar
8 Calder, PC (2006) N-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 83, 1505S1519S.Google Scholar
9 Sano, H, Hla, T, Maier, JAM, et al. (1992) In vivo cyclooxygenase expression in synovial tissues of patients with rheumatoid arthritis and osteoarthritis and rats with adjuvant and streptococcal cell wall arthritis. J Clin Invest 89, 97108.Google Scholar
10 Sperling, RI (1995) Eicosanoids in rheumatoid arthritis. Rheum Dis Clin N Am 21, 741758.Google Scholar
11 Lee, TH, Hoover, RL, Williams, JD, et al. (1985) Effects of dietary enrichment with eicosapentaenoic acid and docosahexaenoic acid on in vitro neutrophil and monocyte leukotriene generation and neutrophil function. N Eng J Med 312, 12171224.Google Scholar
12 Endres, S, Ghorbani, R, Kelley, VE, et al. (1989) The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Eng J Med 320, 265271.Google Scholar
13 Sperling, RI, Benincaso, AI, Knoell, CT, et al. (1993) Dietary ω-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils. J Clin Invest 91, 651660.Google Scholar
14 Gibney, MJ & Hunter, B (1993) The effects of short- and long-term supplementation with fish oil on the incorporation of n-3 polyunsaturated fatty acids into cells of the immune system in healthy volunteers. Eur J Clin Nutr 47, 255259.Google Scholar
15 Caughey, GE, Mantzioris, E, Gibson, RA, Cleland, LG & James, MJ (1996) The effect on human tumor necrosis factor α and interleukin 1β production of diets enriched in n-3 fatty acids from vegetable oil or fish oil. Am J Clin Nutr 63, 116122.Google Scholar
16 Yaqoob, P, Pala, HS, Cortina-Borja, M, Newsholme, EA & Calder, PC (2000) Encapsulated fish oil enriched in α-tocopherol alters plasma phospholipid and mononuclear cell fatty acid compositions but not mononuclear cell functions. Eur J Clin Invest 30, 260274.Google Scholar
17 Healy, DA, Wallace, FA, Miles, EA, Calder, PC & Newsholme, P (2000) The effect of low to moderate amounts of dietary fish oil on neutrophil lipid composition and function. Lipids 35, 763768.Google Scholar
18 Thies, F, Nebe-von-Caron, G, Powell, JR, et al. (2001) Dietary supplementation with γ-linolenic acid or fish oil decreases T lymphocyte proliferation in healthy older humans. J Nutr 131, 19181927.Google Scholar
19 Kew, S, Banerjee, T, Minihane, AM, et al. (2003) Relation between the fatty acid composition of peripheral blood mononuclear cells and measures of immune cell function in healthy, free-living subjects aged 25–72 y. Am J Clin Nutr 77, 12781286.Google Scholar
20 Kew, S, Mesa, MD, Tricon, S, et al. (2004) Effects of oils rich in eicosapentaenoic and docosahexaenoic acids on immune cell composition and function in healthy humans. Am J Clin Nutr 79, 674681.Google Scholar
21 Rees, D, Miles, EA, Banerjee, T, et al. (2006) Dose-related effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men. Am J Clin Nutr 83, 331342.Google Scholar
22 Faber, J, Berkhout, M, Vos, AP, et al. (2011) Supplementation with a fish oil-enriched, high-protein medical food leads to rapid incorporation of EPA into white blood cells and modulates immune responses within one week in healthy men and women. J Nutr 141, 964970.Google Scholar
23 Calder, PC (2008) The relationship between the fatty acid composition of immune cells and their function. Prostagland Leukotr Essent Fatty Acids 79, 101108.Google Scholar
24 Meydani, SN, Endres, S, Woods, MM, et al. (1991) Oral (n-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferation: comparison between young and older women. J Nutr 121, 547555.Google Scholar
25 Von Schacky, C, Kiefl, R, Jendraschak, E & Kaminski, WE (1993) N-3 fatty acids and cysteinyl-leukotriene formation in humans in vitro, ex vivo and in vivo. J Lab Clin Med 121, 302309.Google Scholar
26 Kremer, JM, Bigauoette, J, Michalek, AV, et al. (1985) Effects of manipulation of dietary fatty acids on manifestations of rheumatoid arthritis. Lancet i, 184187.Google Scholar
27 Kremer, JM, Jubiz, W, Michalek, A, et al. (1987) Fish-oil supplementation in active rheumatoid arthritis. Ann Int Med 106, 497503.Google Scholar
28 Kremer, JM, Lawrence, DA, Jubiz, W, et al. (1990) Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Arth Rheum 33, 810820.Google Scholar
29 Sperling, RI, Weinblatt, M, Robin, JL, et al. (1987) Effects of dietary supplementation with marine fish oil on leukocyte lipid mediator generation and function in rheumatoid arthritis. Arth Rheum 30, 988997.Google Scholar
30 Cleland, LG, French, JK, Betts, WH, Murphy, GA & Elliot, MJ (1988) Clinical and biochemical effects of dietary fish oil supplements in rheumatoid arthritis. J Rheumatol 15, 14711475.Google Scholar
31 van der Tempel, H, Tullekan, JE, Limburg, PC, Muskiet, FAJ & van Rijswijk, MH (1990) Effects of fish oil supplementation in rheumatoid arthritis. Ann Rheum Dis 49, 7680.Google Scholar
32 Cleland, LG, Caughey, GE, James, MJ & Proudman, SM (2006) Reduction of cardiovascular risk factors with long term fish oil treatment in early rheumatoid arthritis. J Rheumatol 33, 19731979.Google Scholar
33 Goldman, DW, Pickett, WC & Goetzl, EJ (1983) Human neutrophil chemotactic and degranulating activities of leukotriene B5 (LTB5) derived from eicosapentaenoic acid. Biochem Biophys Res Commun 117, 282288.Google Scholar
34 Lee, TH, Mencia-Huerta, JM, Shih, C, et al. (1984) Characterization and biologic properties of 5,12-dihydroxy derivatives of eicosapentaenoic acid, including leukotriene-B5 and the double lipoxygenase product. J Biol Chem 259, 23832389.Google Scholar
35 Bagga, D, Wang, L, Farias-Eisner, R, Glaspy, JA & Reddy, ST (2003) Differential effects of prostaglandin derived from ω-6 and ω-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion. Proc Natl Acad Sci USA 100, 17511756.Google Scholar
36 Tull, SP, Yates, CM, Maskrey, BH, et al. (2009) Omega-3 Fatty acids and inflammation: novel interactions reveal a new step in neutrophil recruitment. PLoS Biol 7, e1000177.Google Scholar
37 Serhan, CN, Clish, CB, Brannon, J, et al. (2000) Anti-inflammatory lipid signals generated from dietary n-3 fatty acids via cyclooxygenase-2 and transcellular processing: a novel mechanism for NSAID and n-3 PUFA therapeutic actions. J Physiol Pharmacol 4, 643654.Google Scholar
38 Serhan, CN, Clish, CB, Brannon, J, et al. (2000) Novel functional sets of lipid-derived mediators with antinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J Exp Med 192, 11971204.Google Scholar
39 Serhan, CN, Hong, S, Gronert, K, et al. (2002) Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter pro-inflammation signals. J Exp Med 196, 10251037.Google Scholar
40 Hong, S, Gronert, K, Devchand, P, Moussignac, R-L & Serhan, CN (2003) Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood and glial cells: autocoids in anti-inflammation. J Biol Chem 278, 1467714687.Google Scholar
41 Marcheselli, VL, Hong, S, Lukiw, WJ & Hua Tian, X (2003) Novel docosanoids inhibit brain ischemia reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 278, 4380743817.Google Scholar
42 De Caterina, R, Cybulsky, MI, Clinton, SK, Gimbrone, MA & Libby, P (1994) The omega-3 fatty acid docosahexaenoate reduces cytokine-induced expression of proatherogenic and proinflammatory proteins in human endothelial cells. Arterioscler Thromb 14, 18291836.Google Scholar
43 Khalfoun, B, Thibault, F, Watier, H, et al. (1997) Docosahexaenoic and eicosapentaenoic acids inhibit in vitro human endothelial cell production of interleukin-6. Adv Exp Biol Med 400, 589597.Google Scholar
44 Lo, CJ, Chiu, KC, Fu, M, Lo, R & Helton, S (1999) Fish oil decreases macrophage tumor necrosis factor gene transcription by altering the NF kappa B activity. J Surg Res 82, 216221.Google Scholar
45 Babcock, TA, Novak, T, Ong, E, et al. (2002) Modulation of lipopolysaccharide-stimulated macrophage tumor necrosis factor-α production by ω-3 fatty acid is associated with differential cyclooxygenase-2 protein expression and is independent of interleukin-10. J Surg Res 107, 135139.Google Scholar
46 Novak, TE, Babcock, TA, Jho, DH, Helton, WS & Espat, NJ (2003) NF-k kappa B inhibition by omega-3 fatty acids modulates LPS-stimulated macrophage TNF-alpha transcription. Am J Physiol 284, L84L89.Google Scholar
47 Zhao, Y, Joshi-Barve, S, Barve, S, Chen, LH, Barve, S & Chen, LH (2004) Eicosapentaenoic acid prevents LPS-induced TNF-alpha expression by preventing NF-kappaB activation. J Am Coll Nutr 23, 7178.Google Scholar
48 Trebble, T, Arden, NK, Stroud, MA, et al. (2003) Inhibition of tumour necrosis factor-α and interleukin-6 production by mononuclear cells following dietary fish-oil supplementation in healthy men and response to antioxidant co-supplementation. Brit J Nutr 90, 405412.Google Scholar
49 Wallace, FA, Miles, EA & Calder, PC (2003) Comparison of the effects of linseed oil and different doses of fish oil on mononuclear cell function in healthy human subjects. Brit J Nutr 89, 679689.Google Scholar
50 Cooper, AL, Gibbons, L, Horan, MA, Little, RA & Rothwell, NJ (1993) Effect of dietary fish oil supplementation on fever and cytokine production in human volunteers. Clin Nutr 12, 321328.Google Scholar
51 Abbate, R, Gori, AM, Martini, F, et al. (1996) n-3 PUFA supplementation, monocyte PCA expression and interleukin-6 production. Prostagland Leukotr Essent Fatty Acids 54, 439444.Google Scholar
52 Gallai, V, Sarchielli, P, Trequattrini, A, et al. (1995) Cytokine secretion and eicosanoid production in the peripheral blood mononuclear cells of MS patients undergoing dietary supplementation with n-3 polyunsaturated fatty acids. J Neuroimmunol 56, 143153.Google Scholar
53 Thies, F, Miles, EA, Nebe-von-Caron, G, et al. (2001) Influence of dietary supplementation with long-chain n-3 or n-6 polyunsaturated fatty acids on blood inflammatory cell populations and functions and on plasma soluble adhesion molecules in healthy adults. Lipids 36, 11831193.Google Scholar
54 Kew, S, Banerjee, T, Minihane, AM, et al. (2003) Lack of effect of foods enriched with plant- or marine-derived n-3 fatty acids on human immune function. Am J Clin Nutr 77, 12871295.Google Scholar
55 Miles, EA, Banerjee, T, Dooper, MM, M'Rabet, L, Graus, YM & Calder, PC (2004) The influence of different combinations of gamma-linolenic acid, stearidonic acid and EPA on immune function in healthy young male subjects. Brit J Nutr 91, 893903.Google Scholar
56 Blok, WL, Deslypere, JP, Demacker, PN, et al. (1997) Pro- and anti-inflammatory cytokines in healthy volunteers fed various doses of fish oil for 1 year. Eur J Clin Invest 27, 10031008.Google Scholar
57 Molvig, J, Pociot, F, Worsaae, H, et al. (1991) Dietary supplementation with omega-3-polyunsaturated fatty acids decreases mononuclear cell proliferation and interleukin-1 beta content but not monokine secretion in healthy and insulin-dependent diabetic individuals. Scand J Immunol 34, 399410.Google Scholar
58 Cannon, JG, Fiatarone, MA, Meydani, M, et al. (1995) Aging and dietary modulation of elastase and interleukin-1 beta secretion. Am J Physiol 268, R208R213.Google Scholar
59 Esperson, GT, Grunnet, N, Lervang, HH, et al. (1992) Decreased interleukin-1 beta levels in plasma from rheumatoid arthritis patients after dietary supplementation with n-3 polyunsaturated fatty acids. Clin Rheumatol 11, 393395.Google Scholar
60 Kremer, JM, Lawrence, DA, Petrillo, GF, et al. (1995) Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal anti-inflammatory drugs: clinical and immune correlates. Arth Rheum 38, 11071114.Google Scholar
61 Adam, O, Beringer, C, Kless, T, et al. (2003) Antiinflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis. Rheumatol Int 23, 2736.Google Scholar
62 Kolahi, S, Ghorbanihaghjo, A, Alizadeh, S, et al. (2010) Fish oil supplementation decreases serum soluble receptor activator of nuclear factor-kappa B ligand/osteoprotegerin ratio in female patients with rheumatoid arthritis. Clin Biochem 43, 576580.Google Scholar
63 Varming, K, Schmidt, EB, Svaneborg, N, et al. (1995) The effect of n-3 fatty acids on neutrophil chemiluminescence. Scand J Clin Lab Invest 55, 4752.Google Scholar
64 Thompson, PJ, Misso, NLA, Passarelli, M & Phillips, MJ (1991) The effect of eicosapentaenoic acid consumption on human neutrophil chemiluminescence. Lipids 26, 12231226.Google Scholar
65 Luostarinen, R & Saldeen, T (1996) Dietary fish oil decreases superoxide generation by human neutrophils: relation to cyclooxygenase pathway and lysosomal enzyme release. Prostagland Leukotr Essent Fatty Acids 55, 167172.Google Scholar
66 Fisher, M, Levine, PH, Weiner, BH, et al. (1990) Dietary n-3 fatty acid supplementation reduces superoxide production and chemiluminescence in monocyte enriched preparation of leukocytes. Am J Clin Nutr 51, 804808.Google Scholar
67 Schmidt, EB, Varming, K, Moller, JM, Bulow Pederson, I, Madsen, P & Dyerberg, J (1996) No effect of a very low dose of n-3 fatty acids on monocyte function in healthy humans. Scand J Clin Invest 56, 8792.Google Scholar
68 Magaro, M, Altomonte, L, Zoli, A, et al. (1988) Influence of diet with different lipid composition on neutrophil chemiluminescence and disease activity in patients with rheumatoid arthritis. Ann Rheum Dis 47, 793796.Google Scholar
69 Calder, PC & Newsholme, EA (1992) Polyunsaturated fatty acids suppress human peripheral blood lymphocyte proliferation and interleukin-2 production. Clin Sci 82, 695700.Google Scholar
70 Miles, EA, Banerjee, T, Wells, SJ & Calder, PC (2006) Limited effect of eicosapentaenoic acid on T-lymphocyte and natural killer cell numbers and functions in healthy young males. Nutrition 22, 512519.Google Scholar
71 Khair-El-Din, TA, Sicher, SC, Vazquez, MA, Wright, WJ & Lu, CY (1995) Docosahexaenoic acid, a major constituent of fetal serum and fish oil diets, inhibits IFNγ-induced Ia-expression by murine macrophages in vitro. J Immunol 154, 12961306.Google Scholar
72 Hughes, DA, Southon, S & Pinder, AC (1996) (n-3) Polyunsaturated fatty acids modulate the expression of functionally associated molecules on human monocytes in vitro. J Nutr 126, 603610.Google Scholar
73 Calder, PC (2007) Polyunsaturated fatty acids alter the rules of engagement. Future Lipidol 2, 2730.Google Scholar
74 Hughes, DA, Pinder, AC, Piper, Z, Johnson, IT & Lund, EK (1996) Fish oil supplementation inhibits the expression of major histocompatibility complex class II molecules and adhesion molecules on human monocytes. Am J Clin Nutr 63, 267272.Google Scholar
75 Leslie, CA, Gonnerman, WA, Ullman, MD, et al. (1985) Dietary fish oil modulates macrophage fatty acids and decreases arthritis susceptibility in mice. J Exp Med 162, 13361339.Google Scholar
76 Volker, DH, FitzGerald, PEB & Garg, ML (2000) The eicosapentaenoic to docosahexaenoic acid ratio of diets affects the pathogenesis of arthritis in Lew/SSN rats. J Nutr 130, 559565.Google Scholar
77 Ierna, M, Kerr, A, Scales, H, Berge, K & Griinari, M (2010) Supplementation of diet with krill oil protects against experimental rheumatoid arthritis. BMC Musculoskel Disord 11, 136.Google Scholar
78 Fortin, PR, Lew, RA, Liang, MH, et al. (1995) Validation of a metaanalysis: The effects of fish oil in rheumatoid arthritis. J Clin Epidemiol 48, 13791390.Google Scholar
79 MacLean, CH, Mojica, WA & Morton, SC, et al. (2004) Effects of Omega-3 Fatty Acids on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis, Evidence Report/Technical Assessment no. 89 AHRQ Publication no. 04-E012-2. Rockville, MD: Agency for Healthcare Research and Quality; available at http://www.ahrq.gov/clinic/tp/o3lipidtp.htm.Google Scholar
80 Goldberg, RJ & Katz, J (2007) A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain 129, 210233.Google Scholar
81 Jadad, AR, Moore, RA, Carroll, D, et al. (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Contr Clin Trials 17, 112.Google Scholar
82 Belch, JJF, Ansell, D, Madhok, R, O'Dowd, A & Sturrock, RD (1988) Effects of altering dietary essential fatty acids on requirements for non-steroidal anti-inflammatory drugs in patients with rheumatoid arthritis: a double blind placebo controlled study. Ann Rheum Dis 47, 96104.Google Scholar
83 Tullekan, JE, Limburg, PC, Muskiet, FAJ & van Rijswijk, MH (1990) Vitamin E status during dietary fish oil supplementation in rheumatoid arthritis. Arthr Rheum 33, 14161419.Google Scholar
84 Skoldstam, L, Borjesson, O, Kjallman, A, Seiving, B & Akesson, B (1992) Effect of six months of fish oil supplementation in stable rheumatoid arthritis: a double blind, controlled study. Scand J Rheumatol 21, 178185.Google Scholar
85 Nielsen, GL, Faarvang, KL, Thomsen, BS, et al. (1992) The effects of dietary supplementation with n-3 polyunsaturated fatty acids in patients with rheumatoid arthritis: a randomized, double blind trial. Eur J Clin Invest 22, 687691.Google Scholar
86 Kjeldsen-Kragh, J, Lund, JA, Riise, T, et al. (1992) Dietary omega-3 fatty acid supplementation and naproxen treatment in patients with rheumatoid arthritis. J Rheumatol 19, 15311536.Google Scholar
87 Lau, CS, Morley, KD & Belch, JJF (1993) Effects of fish oil supplementation on non-steroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritis. Brit J Rheumatol 32, 982989.Google Scholar
88 Geusens, P, Wouters, C, Nijs, J, Jiang, Y & Dequeker, J (1994) Long-term effect of omega-3 fatty acid supplementation in active rheumatoid arthritis. Arth Rheum 37, 824829.Google Scholar
89 Volker, D, Fitzgerald, P, Major, G & Garg, M (2000) Efficacy of fish oil concentrate in the treatment of rheumatoid arthritis. J Rheumatol 27, 23432346.Google Scholar
90 Remans, PH, Sont, JK, Wagenaar, LW, et al. (2004) Nutrient supplementation with polyunsaturated fatty acids and micronutrients in rheumatoid arthritis: clinical and biochemical effects. Eur J Clin Nutr 58, 839845.Google Scholar
91 Sundrarjun, T, Komindr, S, Archararit, N, et al. (2004) Effects of n-3 fatty acids on serum interleukin-6, tumour necrosis factor-alpha and soluble tumour necrosis factor receptor p55 in active rheumatoid arthritis. J Int Med Res 32, 443454.Google Scholar
92 Berbert, AA, Kondo, CR, Almendra, CL, Matsuo, T & Dichi, I (2005) Supplementation of fish oil and olive oil in patients with rheumatoid arthritis. Nutrition 21, 131136.Google Scholar
93 Galarraga, B, Ho, M, Youssef, HM, et al. (2008) Cod liver oil (n-3 fatty acids) as an non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis. Rheumatol 47, 665669.Google Scholar
94 Dawczynski, C, Schubert, R, Hein, G, et al. (2009) Long-term moderate intervention with n-3 long-chain PUFA-supplemented dairy products: effects on pathophysiological biomarkers in patients with rheumatoid arthritis. Brit J Nutr 101, 15171526.Google Scholar
95 Das Gupta, AB, Hossain, AKMM, Islam, MH, Dey, SR & Khan, MAL (2009) Role of omega-3 fatty acid supplementation with indomethacin in suppression of disease activity in rheumatoid arthritis. Bangladesh Med Res Counc Bull 35, 6368.Google Scholar

Altmetric attention score

Full text views

Full text views reflects PDF downloads, PDFs sent to Google Drive, Dropbox and Kindle and HTML full text views.

Total number of HTML views: 1076
Total number of PDF views: 2980 *
View data table for this chart

* Views captured on Cambridge Core between September 2016 - 17th January 2021. This data will be updated every 24 hours.

Access
Hostname: page-component-77fc7d77f9-wd6lz Total loading time: 1.785 Render date: 2021-01-17T02:31:49.336Z Query parameters: { "hasAccess": "1", "openAccess": "0", "isLogged": "0", "lang": "en" } Feature Flags last update: Sun Jan 17 2021 01:52:19 GMT+0000 (Coordinated Universal Time) Feature Flags: { "metrics": true, "metricsAbstractViews": false, "peerReview": true, "crossMark": true, "comments": true, "relatedCommentaries": true, "subject": true, "clr": true, "languageSwitch": true, "figures": false, "newCiteModal": false, "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true }

Send article to Kindle

To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis
Available formats
×

Send article to Dropbox

To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis
Available formats
×

Send article to Google Drive

To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis
Available formats
×
×

Reply to: Submit a response


Your details


Conflicting interests

Do you have any conflicting interests? *