Correspondence *Neuroimmunology Unit, University of Rochester Medical Center, 601 Elmwood Avenue, Box 605, Rochester, NY 14586, USA

Email lahar_mehta@urmc.rochester.edu

Introduction

The currently approved immunomodulatory therapies for multiple sclerosis (MS) show modest efficacy and can produce a wide range of adverse effects. Interest has, therefore, been increasing in complementary and alternative approaches for the treatment of MS. As disability and impairment accrue, patients with MS often seek unconventional treatments in the hope of halting the disease process.¹ One popular unconventional approach is dietary supplementation with polyunsaturated fatty acids (PUFAs). In view of the reputed anti-inflammatory properties of PUFAs, numerous reviews have cited these agents as potential treatments for immune-mediated disorders, including rheumatoid arthritis and MS.^{2, 3, 4, 5, 6, 7} In a recent survey, 37% of 1,573 patients with MS revealed that they had used omega-3 unsaturated fatty acids at some point in their lives.⁸

In this Review, we briefly discuss the nomenclature of PUFAs, as well as describing their sources and derivatives. We then describe epidemiologic studies that have indicated a link between dietary saturated and polyunsaturated fat intake and the risk and severity of MS. These results have contributed to an increased interest in the biological effects of PUFAs in inflammation. We then discuss the effects of PUFAs in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Finally, we review the noncontrolled and controlled clinical trials that have assessed the effect of PUFA administration on disability and relapses in MS. We conclude by discussing the implications of all these findings for further clinical research into the effects of PUFAs in MS.

Polyunsaturated fatty acids: an overview

Polyunsaturated fatty acids (PUFAs) are defined as fatty acids that possess more than two carbon–carbon double bonds. Given that they also contain 18 or more carbon atoms, they are often referred to as long-chain PUFAs. The term omega or n refers to the terminal methyl end of the fatty acid. The numerical designation, such as omega-3 or n-3, refers to the location of the last carbon–carbon double bond from the omega end. For the purposes of this Review, we will use the omega designation to distinguish the two classes of fatty acids, and the term PUFAs to refer to either omega-3 or omega-6 fatty acids.

Omega-3 and omega-6 PUFAs and their derivatives have important roles in metabolic, immunologic, coagulation and inflammatory processes. Omega-3 PUFAs are primarily derived from fish oils, whereas omega-6 PUFAs are obtained from plant sources, including sunflower, safflower, corn, wheat germ and soybean oils (Figure 1). Omega-3 PUFAs, such as -linolenic acid, are converted, through several reactions, to eicosapentanoic acid (EPA). However, EPA can also be directly obtained through the diet from fish oils. EPA can be converted to docohexanoic acid (DHA), and also to eicosanoids, such as prostaglandins, thromboxanes and leukotrienes, which are essential for inflammatory signaling. DHA is converted to eicosanoids, and, ultimately, to anti-inflammatory mediators such as resolvins and protectins.

Figure 1 Omega-6 and omega-3 PUFAs and their respective sources and metabolic derivatives.

After consumption, the PUFAs are metabolized via several pathways (not shown) to active compounds that mediate inflammation and products that promote resolution of inflammation. Possible effects on inflammation are listed in the box at the bottom. Abbreviations: IFN-, interferon ; IL-2, interleukin 2; NFB, nuclear factor kappa B; PGE₂, prostaglandin E₂; PPAR, peroxisome proliferator-activated receptor ; PUFAs, polyunsaturated fatty acids; TGF, transforming growth factor ; TNF, tumor necrosis factor.

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Omega-6 PUFAs are more abundant in the diet than omega-3 PUFAs. Omega-6 PUFAs are converted to other metabolites through various enzymatic processes, and eventually to the key intermediate arachidonic acid, which is subsequently converted to eicosanoids. Omega-3 PUFAs tend to be more potent anti-inflammatory agents than omega-6 PUFAs, but the effects of omega-6 PUFAs might predominate owing to the abundance of these compounds in the diet.⁹

Studies exploring diet and multiple sclerosis risk

Epidemiologic studies have reported that MS is particularly common in geographic regions with high levels of saturated fat consumption. However, these findings were derived mainly from ecological studies, which are highly susceptible to confounding factors.¹⁰ Analysis of data pooled from 36 industrialized nations showed that saturated fatty acids, animal fat and animal minus fish fat were all independent predictors of MS mortality (P <0.001 in women and P <0.01 in men). Furthermore, the ratios of dietary polyunsaturated to saturated fatty acids and of monounsaturated plus polyunsaturated to saturated fatty acids showed independent and significant negative correlations with the risk of developing MS (P <0.01–P <0.001 in women, and P <0.05–P <0.01 in men).¹¹ A multivariate analysis of published data from 48 states in the US found positive correlations between the risk of MS and the sales of meat and dairy products. By contrast, an inverse correlation was evident between MS risk and the sales of vegetable and fish products.¹²

Numerous case–control studies on diet and MS have been conducted over the past 60 years. However, the results of these studies were inconsistent, and did not support an overall relationship between fat intake and MS.^{13, 14, 15, 16, 17}The inconsistencies probably stem from the retrospective nature of the studies, which renders them vulnerable to bias. Another potential weakness of such studies is their susceptibility to confounding factors.¹⁰ A recent case-control study in Norway found an inverse association between fish intake and risk of developing MS.¹⁸ The investigators believe that vitamin D, which is highly concentrated in cod-derived products, might have confounded the results of previous observational studies. Vitamin D has an important role in the immune system, and high levels have been associated with a reduced risk of developing MS.^{19, 20, 21}

Despite the results from case-control and ecological studies, a large prospective study that analyzed data from two large cohorts (150,000 women, including 195 incident cases of MS) in the Nurses' Health Studies I and II failed to find any evidence that an increased risk of MS was associated with high intake of saturated fats or a low intake of polyunsaturated fats.²² A borderline inverse association was noted between linolenic acid intake and risk of MS, but this link was nonsignificant. This longitudinal study design is much less susceptible to recall or selection bias than are case-control and ecological studies.¹⁰

Several small studies have demonstrated a reduction in PUFA content in serum, cerebral white matter, erythrocytes and lymphocytes in patients with MS compared with controls.^{23, 24, 25, 26} However, these observations do not help to clarify the exact nature of the relationship between PUFA intake and MS, as no data were provided on the dietary habits and clinical characteristics of the study participants.

Effects of polyunsaturated fatty acids on inflammation

The relationship between dietary fat intake and the risk of MS remains unclear, but evidence is growing that omega-6 and omega-3 PUFAs have anti-inflammatory effects. This evidence derives from the results of several in vitro, in vivo and ex vivo studies that are likely to be relevant to MS. The anti-inflammatory effects of omega-3 and omega-6 PUFAs might include competitive inhibition of arachidonic acid, the metabolites of which are involved in promoting inflammation.^{27, 28, 29} In addition, the production of anti-inflammatory prostaglandins E₁ and E₂, which are derived from the omega-6 PUFA dihomo--linolenic acid, can inhibit the production of proinflammatory cytokines such as interleukin (IL)-2 and interferon (IFN-).^{30, 31, 32}  In vitro, T-cell proliferation can be reduced by supplementation with either omega-6 or omega-3 PUFAs.³³ Both omega-6 and omega-3 PUFAs can modify lymphocyte function through a reduction in the levels of the proinflammatory cytokines IL-1, tumor necrosis factor (TNF) and IL-1.^{34, 35, 36} Omega-3 PUFAs might also inhibit the migratory activity of leukocytes—an essential part of the inflammatory response—via alteration of cytoskeletal components.³⁷

Recently identified molecules derived from PUFAs have roles in the resolution of inflammation. These molecules include lipoxins, which are derived from arachidonic acid and can promote resolution of inflammation by reducing neutrophil activity and stimulating the uptake of apoptotic polymorphonuclear leukocytes.³⁸ Resolvins and protectins are two other types of lipid mediator that are derived from omega-3 PUFAs, EPA and DHA, via lipooxygenase-mediated mechanisms.^{39, 40, 41} D-series resolvins (those derived from DHA) are attractive candidates for the control of inflammation in neural tissues, given that these tissues are a source of endogenous DHA. Effects of D-resolvins include inhibition of neutrophil activity and, potentially, modulation of inflammation.^{39, 42} Protectins are also derived from DHA, and protectin D₁ in particular possesses anti-inflammatory properties that include reduction of TNF expression and IFN- production, and promotion of T-cell apoptosis.^{39, 43}

Increasing attention is being paid to the roles of PUFAs as ligands for peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated nuclear transcription factors that have various subtypes. PPARs regulate genes that are involved in lipid metabolism and lipid storage, and have important roles in the anti-inflammatory response.^{44, 45} PUFAs and their respective derivatives can serve as PPAR agonists.^{45, 46, 47} Human T lymphocytes express the PPAR isoform, and omega-3 PUFAs and their eicosanoid derivatives are thought to possess stronger PPAR-agonist properties than omega-6 PUFAs and their derivatives.⁴⁸ Oral administration of PPAR agonists can not only ameliorate existing inflammation in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, but can also prevent inflammation from occurring in such models.^{49, 50, 51} These findings suggest a potential role for PPAR agonists in the treatment of MS.⁵²

Omega-3 PUFAs have also recently been shown to inhibit the expression of nuclear factor B (NFB), a transcription factor that is crucial for the production of inflammatory cytokines, chemokines and adhesion molecules with pivotal roles in MS.^{53, 54, 55, 56}

In addition, omega-3 PUFAs can, in vivo, promote the production of molecules involved in myelinogenesis.⁵⁷ When EPA and DHA were injected intraventricularly into rat brains, increased expression of gene transcripts for proteolipid protein, mylein basic protein and myelin oligodendrocyte was observed. The investigators showed that EPA adminstration caused a more pronounced effect than administration of DHA.

PUFAs might also alter the production of certain matrix metalloproteinases (MMPs) that have been implicated in disruption of the blood–brain barrier. MMP activity seems to facilitate the migration of leukocytes into the CNS. Dietary supplementation with conjugated linoleic acid and DHA in rats reduced serum levels of MMP2 and MMP9.⁵⁸ Various doses of omega-3 PUFAs (DHA and EPA) alone, or of a mixture of DHA, EPA, linoleic acid, arachidonic acid and saturated fatty acids, can lower MMP9 levels when added to lipopolysaccharide-stimulated rat microglial cell cultures.⁵⁹

Trials of polyunsaturated fatty acids in multiple sclerosis

Clinical trials

Noncontrolled observations

Over 50 years ago, Swank hypothesized that dietary fat intake contributed to disability progression in MS.^{65, 66, 67, 68, 69} In what was essentially an open-label observational study, Swank prescribed a low-fat diet to patients with relapsing–remitting MS, in which fats derived from dairy and animal sources were gradually eliminated, and replaced with both omega-3 and omega-6 fatty acids derived from fish and vegetable sources. The patients (n = 47) showed reductions in the frequency and severity of exacerbations—usually after the first year of observation had elapsed—and continued to demonstrate improvements in relapse rate and severity after 5.5 years.^{65, 66} Those who adhered most closely to the prescribed diet seemed to derive the greatest benefits from the intervention, and no adverse events were reported. The patients were monitored over the next 15 years, and maintained lower levels of disease activity and disability than would be predicted by natural history studies—this was true especially of those who began to follow the diet early in their disease course.⁶⁷ In 2000, 15 patients who had been on the diet for 50 years were re-evaluated, and 13 of these individuals were described as ambulatory and fully able to perform activities of daily living.⁶⁹

In another noncontrolled trial, patients with MS (n = 12) who were treated with a combination of EPA and DHA omega-3 PUFAs for 4 months showed minimal change in disability as a group. However, the subset with relapsing–remitting disease (n = 5) showed a decrease in their mean Expanded Disability Status Scale (EDSS) score from 3.30 to 2.70, whereas those with progressive disease (n = 7) showed an increase in mean EDSS score from 6.42 to 7.07.⁷⁰ In a similar study, 16 patients with relapsing–remitting MS were treated with fish oil containing DHA and EPA for 2 years.⁷¹ The investigators also provided dietary advice to reduce daily saturated fat intake and increase weekly fish consumption. At the end of 2 years, a significant reduction in mean annual relapse rate and mean EDSS score (P <0.01) was evident when compared with baseline assessments. Serum concentrations of omega-3 fatty acids had also increased significantly (P <0.001).

Controlled trials

In an attempt to provide a proper assessment of the efficacy of PUFA supplementation in MS, multiple controlled studies have been performed, some of which date back to the 1970s. These studies, however, generally produced inconclusive results.⁷² The results of the controlled trials performed to date are summarized in Table 1.

Table 1 Clinical trials that assessed the efficacy of polyunsaturated fatty acid supplementation in MS.

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In a double-blind study by Millar et al., 75 patients with MS were randomly assigned to receive linoleic acid (administered in the form of sunflower seed oil) or oleic acid (an omega-9 PUFA with no known immunomodulatory effects, administered in the form of olive oil) as a control. The authors monitored the effects of this treatment for 2 years.⁷³ A nonsignificant trend towards lower annualized relapse rates and a significant reduction in relapse severity (P <0.01) were identified in the linoleic acid group compared with the control group. Relapse severity was measured on the basis of a semiquantitative assessment of the type and duration of specific symptoms. Disability status was scored by a modified Kurtzke Disability Status Scale (DSS) and by patients' ability to perform activities of daily living.^{73, 74, 75} Disability in both groups worsened to similar degrees, and no overall differences were observed between the groups. The investigators reported contrasting trends between the study sites, but did not elaborate any further on this point.⁷³

In a 2-year study, Bates et al. randomly allocated 152 patients with chronic, progressive MS to one of four groups.⁷⁶ One group received a combination of linoleic acid and GLA in the form of Naudicelle^® oil capsules (Naudicelle Ltd, Nantwich, Cheshire, UK) and a second received placebo (oleic acid capsules). Two additional groups received spreads containing linoleic acid or oleic acid. No significant differences were observed in disability (measured by the DSS), relapse rates, or the relapse severity score as used in Millar et al.'s study.⁷³ In a separate trial, Bates et al. randomly assigned 116 patients with relapsing MS to one of the four treatment arms.⁷⁷ The linoleic acid–GLA group had shorter, less-severe relapses than did the oleic acid group, although the methods used to obtain this outcome were not fully described. The linoleic acid–GLA acid group showed more progression of disability than did the oleic acid group (P <0.05). Linoleic acid spread alone was significantly associated with attacks that were shorter in duration, and was also associated with lower attack severity scores.

Paty et al. randomly assigned 96 patients with relapsing or progressive MS to linoleic acid or oleic acid for 30 months of double-blind treatment. This study monitored the effects of this treatment on disability (DSS, Kurtzke functional scales), relapse-related measures, and results of timed functional studies (7 timed tests of upper extremity function conducted by an occupational therapist, and 46 timed tests of upper and lower extremity functions carried out by a physical therapist).^{74, 78, 79, 80} Compared with placebo, linoleic acid did not affect disability, relapse rates, relapse severity, or the outcomes of functional tests, despite a marked increase in the serum concentration of linoleic acid in the treated group.^{79, 80}

The inconsistent results of these studies prompted Dworkin et al. to reanalyze pooled data from three of the four sites (Belfast, Newcastle upon Tyne and Western Ontario, but not London) that enrolled patients in these studies.^{73, 77, 79} A total of 87 patients treated with linoleic acid and 85 controls were examined, and assessments from the first 30 months after treatment initiation were included in the analysis.⁸¹ Dworkin and colleagues hypothesized that the benefits of linoleic acid supplementation would be most pronounced in patients with minimal disability or a short disease duration at baseline. This hypothesis was tested by comparing patients who, at trial entry, had lower (0–2) versus higher (3–6) disability scores, and different durations of disease (0–5 years, 6–10 years or 11 years). The results showed a benefit of linoleic acid with respect to disability progression in patients with minimal or no disability at trial entry; the DSS score showed mean changes of 0.12 in the linoleic acid group and 0.81 in the control group (P = 0.05, one-tailed Mann–Whitney U test). In addition, treatment with linoleic acid reduced the severity and duration of relapses at all levels of disability and disease duration. Considered together, the results of these three trials and the analysis of the pooled data provide support for a beneficial effect of linoleic acid, or the combination of linoleic acid plus linolenic acid, in reducing the severity of relapses and the rate of disease progression in patients with MS.

In a separate trial, Bates et al. randomly assigned 312 patients with relapsing MS to receive either a mixture of omega-3 fatty acids (18% EPA, 12% DHA) derived from fish oil or to placebo (primarily oleic acid) for 2 years.⁸² Both groups were also instructed to restrict saturated fat intake and to increase the intake of omega-6 PUFAs in their diets. The fish-oil group demonstrated a trend towards less disability progression (on the basis of DSS scores) compared with placebo (P = 0.07). In a prespecified subgroup analysis, no difference was evident in disability changes between the fish oil and placebo groups for patients with DSS scores 2 or with MS of 5 years' duration. Furthermore, no significant difference was evident between the fish oil and placebo groups with regard to the frequency, duration or severity of relapses.

Weinstock-Guttman et al. randomly assigned 31 patients with MS to omega-3 PUFAs from fish oil or to placebo.⁸³ All patients were also instructed to maintain a low intake of saturated fat. The group taking omega-3 PUFAs showed improvements in quality-of-life measures (SF-36^®[Medical Outcomes Trust, Inc., Waltham, MA] Physical Component Scale and the Mental Health Inventory) compared with the placebo group after 6 months of treatment, but not after 12 months. No differences in relapse rates were observed between the two groups.

In 2008, Harbige et al. described the results of a randomized, double-blind, placebo-controlled trial to determine the effects of two different dosages of BGC20-884, a GLA-rich oil derived from borage oil, in patients with active MS.⁸⁴ A total of 28 patients were followed over 18 months. High-dose GLA treatment (14 g per day; 11 patients) significantly reduced relapse rates (P < 0.05) when compared with placebo (10 patients) and low-dose GLA (5 g per day; 7 patients). The high-dose GLA treatment group also showed reduced disability progression, as measured with the EDSS. However, the authors did not provide detailed information regarding trial design, statistical methods, and the characteristics of the patients.

Limitations of the trials performed to date

The inconsistent results from the clinical trials performed to date are disappointing, but we believe that these trials possess several notable limitations. First, we consider the question of appropriate clinical trial design. The observational and noncontrolled trials mentioned above were extremely prone to selection bias. Furthermore, noncontrolled studies give no indication as to how individuals with MS would have fared had the disease been allowed to take its natural course. A matched control cohort can also help eliminate problems caused by regression to the mean, which is common in MS clinical trials.⁸⁵ In patients with MS who have a high level of disease activity, such as frequent relapses, these parameters will tend to return to the average when followed longitudinally. One recent study of 44 patients with relapsing–remitting MS reported that regression to the mean can reduce the relapse rate by as much as 40%.⁸⁶ In extension studies such as those performed by Swank et al., individuals who persisted with PUFA supplementation might have had a mild course of disease.⁶⁹ Conversely, individuals who were lost to follow up might have had a persistent course of MS that was refractory to diet modification.

Randomized, placebo-controlled trials are often preferable for the demonstration of efficacy in clinical trial research, as they have the design least susceptible to bias. However, these trials have limitations of their own. The randomized, controlled trials that have assessed the efficacy of various PUFAs typically contained small sample sizes, which reduced their power to detect small effects and adverse events. Some studies included both patients with relapsing MS and patients with chronic, progressive disease. Given that these two groups have very different patterns of disease (patients with progressive MS experience relapses to a lesser extent), the outcome measures that were used in these trials might not detect a significant benefit. Indeed, the choice of different and often inadequately validated outcome measures for the various trials might have limited their ability to detect meaningful differences overall. Some of the rating scales used in the early controlled trials, such as those used to measure relapse severity, had not been validated and were not widely employed at the time. Another common limitation lies in the fact that disability measures in MS, such as the DSS and EDSS, are often insensitive to changes that occur over a short time scale. Disability often accrues gradually, and 1–2-year studies are generally insufficient to provide any meaningful data on a treatment-related effect of PUFAs. Another issue is the ability to achieve appropriate statistical power to detect a true difference effect between treatment and control groups. Power is increased with large sample sizes or long study durations. Thus, studies with small numbers of patients conducted over a 1–2-year period are likely to be underpowered.

Another limitation in the controlled trials relates to the choice of an appropriate placebo. In most of the controlled trials mentioned above, olive oil was used as a placebo in the belief that oleic acid is relatively inert.^{73, 76, 77, 80, 82, 83} However, some evidence exists that components in olive oil inhibit NF-B activation.⁸⁷ Furthermore, oleanic acid, which is also found in olive oil, can induce the release of prostacyclin, which can in turn activate PPAR.^{88, 89} These observations suggest that olive oil might not be an ideal placebo for PUFA trials, a factor that might partially explain the apparent lack of efficacy of PUFAs in the aforementioned trials.

Finally, relative uncertainty exists in relation to the optimal dosing of omega-3 and omega-6 PUFAs. The trials described above assessed various formulations, dosages and delivery vehicles for PUFAs, which hinders the attempt to draw any meaningful conclusions about safety and tolerability.⁷² The optimal balance between omega-6 and omega-3 intake is also unknown. Both types of PUFAs competitively use the same set of enzymes, and the omega-6:omega-3 ratio in cell membranes can affect cell fluidity, which could in turn have a marked effect on numerous cellular functions.⁴⁸ Furthermore, omega-3 and omega-6 PUFAs might have proinflammatory properties under certain conditions.^{90, 91}

Implications for future research

The recent identification of mechanisms that indicate that omega-6 and omega-3 PUFAs might have beneficial effects on immune function should be explored with conventional proof-of-concept studies that use MRI end points. In particular, the incidence of gadolinium-enhancing brain lesions has emerged as a particularly sensitive measure of anti-inflammatory potential in preliminary proof-of-concept trials.⁹²

Studies that examine such MRI activity have several inherent advantages: reduction of intrapatient variability, minimization of the number of potentially uninformative MRI scans, an adequate statistical power despite a relatively low number of patients, and a short study duration.^{93, 94} As a consequence, additional resources could be allocated for dose-ranging studies and controlled phase III trials that employ definitive clinical end points, in an attempt to demonstrate therapeutic effects of omega-3 or omega-6 PUFAs in MS.

Conclusions

There are some indications that PUFA intake has an inverse relationship with MS risk, but the controlled studies performed to date have not produced definitive results with regard to the potential benefits of PUFA supplementation in patients with MS. To address such potential benefits, well-designed, relatively short proof-of-concept trials with MRI end points are needed. Any successful result should then be followed by substantially larger and longer-term confirmatory trials with clinical end points.

Acknowledgments

The authors dedicate this article to the memory of Steven R Schwid, whose unparalleled commitment to the care of patients with multiple sclerosis and to discovering improved treatments for this disorder is an enduring inspiration.LR Mehta is supported by a Sylvia Lawry Physician Fellowship Award from the National Multiple Sclerosis Society.

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Subject areas under which this article appears: Neuroimmunology and neuroinflammation