Gruenwald J, Graubaum JH, Harde A. Effect of cod liver oil on symptoms of rheumatoid arthritis. Adv Ther,2002;19(2):101-107.

In this pilot study, 43 patients with rheumatoid arthritis ingested 1 g of cod liver oil (one capsule) daily for 3 months.

Decreases occurred in morning stiffness (52.4%; P<10(-3)), painful (42.7%) and swollen (40%) joints (P= 10(-3) each), and pain intensity (67.5%). Ratings of "good" or "very good" were awarded by 68% of the patients for efficacy and by 95% for tolerability.

Eleven patients reported nonsevere adverse effects that in 3 cases may have been related to the study preparation.

Cod liver oil can be recommended for the treatment of rheumatoid arthritis.

Trebble T, Wootton S, et al. Prostaglandin E2 production and T cell function after fish-oil supplementation: response to antioxidant co-supplementation. Am J Clin Nutr 2003;78(3):376-382

Background: Prostaglandin E2 (PGE2) inhibits lymphocyte proliferation and the production of interferon-gamma (IFN-gamma) by peripheral blood mononuclear cells, but the effect of PGE2 on interleukin 4 (IL-4) production is unclear.

Fish oil, which contains eicosapentaenoic and docosahexaenoic acids, inhibits production of PGE2. The effects of fish oil on lymphocyte proliferation and production of IFN-gamma and IL-4 are unclear and may be influenced by the availability of antioxidants.

Objective: We investigated the effect of dietary fish oil with and without antioxidant cosupplementation on lymphocyte proliferation and the production of PGE2, IFN-gamma, and IL-4 by peripheral blood mononuclear cells.

Design: Sixteen healthy men received dietary fish-oil supplements providing 0.3, 1, and 2 g eicosapentaenoic acid plus docosahexaenoic acid/d for 4 consecutive weeks each (total of 12 wk). All subjects were randomly assigned to daily cosupplementation with either antioxidants (200 µg Se, 3 mg Mn, 30 mg RRR-alph-tocopheryl succinate, 90 mg ascorbic acid, 450 µg vitamin A) or placebo.

Results: Fish-oil supplementation decreased PGE2 production and increased IFN-gamma production and lymphocyte proliferation from baseline values. Cosupplementation with antioxidants did not affect cytokine production or lymphocyte proliferation.

Conclusion: Dietary fish oil modulates production of IFN-gamma and lymphocyte proliferation in a manner consistent with decreased production of PGE2, but this effect is not modified by antioxidant cosupplementation.

Calder P. n-3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clinical Nutr, 2006;83(6):S1505-1519S.

Inflammation is part of the normal host response to infection and injury. However, excessive or inappropriate inflammation contributes to a range of acute and chronic human diseases and is characterized by the production of inflammatory cytokines, arachidonic acid-derived eicosanoids (prostaglandins, thromboxanes, leukotrienes, and other oxidized derivatives), other inflammatory agents (eg, reactive oxygen species), and adhesion molecules.

At sufficiently high intakes, long-chain n-3 polyunsaturated fatty acids (PUFAs), as found in oily fish and fish oils, decrease the production of inflammatory eicosanoids, cytokines, and reactive oxygen species and the expression of adhesion molecules.
Long-chain n-3 PUFAs act both directly (eg, by replacing arachidonic acid as an eicosanoid substrate and inhibiting arachidonic acid metabolism) and indirectly (eg, by altering the expression of inflammatory genes through effects on transcription factor activation).
Long-chain n-3 PUFAs also give rise to a family of antiinflammatory mediators termed resolvins.

Thus, n-3 PUFAs are potentially potent antiinflammatory agents.

As such, they may be of therapeutic use in a variety of acute and chronic inflammatory settings. Evidence of their clinical efficacy is reasonably strong in some settings (eg, in rheumatoid arthritis) but is weak in others (eg, in inflammatory bowel diseases and asthma). More, better designed, and larger trials are required to assess the therapeutic potential of long-chain n-3 PUFAs in inflammatory diseases.

The precursor n-3 PUFA -linolenic acid does not appear to exert antiinflammatory effects at achievable intakes.

Simopoulos AP. Omega-3 fatty acids in health and disease and in growth and development. Am J Clin Nut 1991;54:438-463.

Several sources of information suggest that man evolved on a diet with a ratio of omega 6 to omega 3 fatty acids of approximately 1 whereas today this ratio is approximately 10:1 to 20-25:1, indicating that Western diets are deficient in omega 3 fatty acids compared with the diet on which humans evolved and their genetic patterns were established. Omega-3 fatty acids increase bleeding time; decrease platelet aggregation, blood viscosity, and fibrinogen; and increase erythrocyte deformability, thus decreasing the tendency to thrombus formation.

In no clinical trial, including coronary artery graft surgery, has there been any evidence of increased blood loss due to ingestion of omega 3 fatty acids.

Many studies show that the effects of omega 3 fatty acids on serum lipids depend on the type of patient and whether the amount of saturated fatty acids in the diet is held constant.
In patients with hyperlipidemia, omega 3 fatty acids decrease low-density-lipoprotein (LDL) cholesterol if the saturated fatty acid content is decreased, otherwise there is a slight increase, but at high doses (32 g) they lower LDL cholesterol; furthermore, they consistently lower serum triglycerides in normal subjects and in patients with hypertriglyceridemia whereas the effect on high-density lipoprotein (HDL) varies from no effect to slight increases.

The discrepancies between animal and human studies most likely are due to differences between animal and human metabolism. In clinical trials eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the form of fish oils along with antirheumatic drugs improve joint pain in patients with rheumatoid arthritis; have a beneficial effect in patients with ulcerative colitis; and in combination with drugs, improve the skin lesions, lower the hyperlipidemia from etretinates, and decrease the toxicity of cyclosporin in patients with psoriasis.

In various animal models omega 3 fatty acids decrease the number and size of tumors and increase the time elapsed before appearance of tumors.

Studies with nonhuman primates and human newborns indicate that DHA is essential for the normal functional development of the retina and brain, particularly in premature infants.

Because omega 3 fatty acids are essential in growth and development throughout the life cycle, they should be included in the diets of all humans.

Omega-3 and omega 6 fatty acids are not interconvertible in the human body and are important components of practically all cell membranes.

Whereas cellular proteins are genetically determined, the polyunsaturated fatty acid (PUFA) composition of cell membranes is to a great extent dependent on the dietary intake.

Belch JJF, Hill A. Evening primrose oil and borage oil in rheumatologic conditions. Am. J. Clinical Nutrition, 2000;71 (1): 352S-356S.

Diets rich in arachidonic acid (20:4n-6) lead to the formation of 2-series prostaglandins (PGs) and 4-series leukotrienes (LTs), with proinflammatory effects.

Nonsteroidal antiinflammatory drugs are used in rheumatoid arthritis to inhibit cyclooxygenase (prostaglandin-endoperoxide synthase), thereby decreasing production of 2-series PGs. Lipoxygenase activity remains intact, however, allowing LT production (eg, synthesis of LTB4, a potent inflammatory mediator) to continue.

Altering the essential fatty acid (EFA) content of the diet can modify some of these effects.

Ingestion of a diet rich in evening primrose oil elevates concentrations of dihomo--linolenic acid (DGLA; 20:3n-6), which results in the production of 1-series PGs, eg, PGE1. DGLA itself cannot be converted to LTs but can form a 15-hydroxyl derivative that blocks the transformation of arachidonic acid to LTs. Increasing DGLA intake may allow DGLA to act as a competitive inhibitor of 2-series PGs and 4-series LTs and thus suppress inflammation.

The results of in vitro and animal work evaluating EFAs in inflammatory situations are encouraging, which has stimulated clinical workers to evaluate these compounds in rheumatoid arthritis.

Several well-controlled, randomized clinical studies have now been completed in which various EFAs were evaluated as treatments. The results of most of these studies suggest some clinical benefit to these treatments; these data are reviewed here.

Kremer JM. n-3 Fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr.,2000;71(1):349S-351S.

Ingestion of dietary supplements of n-3 fatty acids has been consistently shown to reduce both the number of tender joints on physical examination and the amount of morning stiffness in patients with rheumatoid arthritis.

In these cases, supplements were consumed daily in addition to background medications and the clinical benefits of the n-3 fatty acids were not apparent until they were consumed for 12 wk.

It appears that a minimum daily dose of 3 g eicosapentaenoic and docosahexaenoic acids is necessary to derive the expected benefits.

These doses of n-3 fatty acids are associated with significant reductions in the release of leukotriene B4 from stimulated neutrophils and of interleukin 1 from monocytes.

Both of these mediators of inflammation are thought to contribute to the inflammatory events that occur in the rheumatoid arthritis disease process.

Several investigators have reported that rheumatoid arthritis patients consuming n-3 dietary supplements were able to lower or discontinue their background doses of nonsteroidal antiinflammatory drugs or disease-modifying antirheumatic drugs. Because the methods used to determine whether patients taking n-3 supplements can discontinue taking these agents are variable, confirmatory and definitive studies are needed to settle this issue.

n-3 Fatty acids have virtually no reported serious toxicity in the dose range used in rheumatoid arthritis and are generally very well tolerated.

Ziboh VA, Fletcher MP. Dose-response effects of dietary gamma-linolenic acid-enriched oils on human polymorphonuclear-neutrophil biosynthesis of leukotriene B4. Am J Clinical Nutr.,1992;55:39-45.

The dose-dependent effect of dietary supplemented gamma-linolenic acid (GLA, 18:3n-6)-enriched borage oil (Bor) and black-currant oil on the ability of calcium ionophore-activated human polymorphonuclear neutrophils (PMN) to generate leukotriene B4 (LTB4) was investigated in adult healthy human volunteers.

Significant (P less than 0.05) elevation of dihomo-gamma-linolenic acid (DGLA, 20:3n-6), an elongation product of GLA, was revealed in PMN phospholipids after ingestion of either 0.48 or 1.5 g GLA-enriched oil/d.

This elevation of DGLA in the PMN phospholipids paralleled the decreased capacity of calcium ionophore-activated PMN to generate LTB4.

Although the inhibition of LTB4 was greater with the ingestion of 1.5 g GLA-enriched BOR/d, it was not significantly different from the ingestion of 0.48 g/d.

Taken together, dietary ingestion of GLA-fortified oils does modulate PMN generation of proinflammatory LTB4.

Calder P, Zurier R. Polyunsaturated fatty acids and rheumatoid arthritis.Curr Opin Clin Nutr Metab Care, Mar 2001; 4(2): 115-21

Rheumatoid arthritis is characterized by infiltration of T lymphocytes, macrophages and plasma cells into the synovium, and the initiation of a chronic inflammatory state that involves overproduction of proinflammatory cytokines and a dysregulated T-helper-1-type response.

Eicosanoids synthesized from arachidonic acid and cytokines cause progressive destruction of cartilage and bone. The n-6 polyunsaturated fatty acid gamma-linolenic acid is the precursor of di-homo-gamma-linolenic acid.

The latter and the n-3 polyunsaturated fatty acid eicosapentaenoic acid, which is found in fish oil, are able to decrease the production of arachidonic acid-derived eicosanoids and to decrease the production of proinflammatory cytokines and reactive oxygen species, and the reactivity of lymphocytes.

A number of double-blind, placebo-controlled trials of gamma-linolenic acid and fish oil in rheumatoid arthritis have shown significant improvements in a variety of clinical outcomes.

These fatty acids should be included as part of the normal therapeutic approach to rheumatoid arthritis. However, it is unclear what the optimal dosage of the fatty acids is, or whether there would be extra benefit from using them in combination.

Cleland LG, James MJ, Proudman SM. The role of fish oils in the treatment of rheumatoid arthritis. Drugs,2003;63(9):845-853.

Fish oils are a rich source of omega-3 long chain polyunsaturated fatty acids (n-3 LC PUFA). The specific fatty acids, eicosapentaenoic acid and docosahexaenoic acid, are homologues of the n-6 fatty acid, arachidonic acid (AA).

This chemistry provides for antagonism by n-3 LC PUFA of AA metabolism to pro-inflammatory and pro-thrombotic n-6 eicosanoids, as well as production of less active n-3 eicosanoids.

In addition, n-3 LC PUFA can suppress production of pro-inflammatory cytokines and cartilage degradative enzymes.

In accordance with the biochemical effects, beneficial anti-inflammatory effects of dietary fish oils have been demonstrated in randomised, double-blind, placebo-controlled trials in rheumatoid arthritis (RA).

Also, fish oils have protective clinical effects in occlusive cardiovascular disease, for which patients with RA are at increased risk. Implementation of the clinical use of anti-inflammatory fish oil doses has been poor. Since fish oils do not provide industry with the opportunities for substantial profit associated with patented prescription items, they have not received the marketing inputs that underpin the adoption of usual pharmacotherapies.
Accordingly, many prescribers remain ignorant of their biochemistry, therapeutic effects, formulations, principles of application and complementary dietary modifications.

Evidence is presented that increased uptake of this approach can be achieved using bulk fish oils. This approach has been used with good compliance in RA patients.

In addition, an index of n-3 nutrition can be used to provide helpful feedback messages to patients and to monitor the attainment of target levels. Collectively, these issues highlight the challenges in advancing the use of fish oil amid the complexities of modern management of RA, with its emphasis on combination chemotherapy applied early.

Watkins B, Li Y, Lippman H,and Seifert M. Experimental Biology and Medicine 2001,226:485-497

Omega-3 Polyunsaturated Fatty Acids and Skeletal Health

This minireview on skeletal biology describes the actions of prostaglandins and cytokines involved in the local regulation of bone metabolism, it documents the role of lipids in bone biology, and it presents relationships between fatty acids and other factors that impact skeletal metabolism. The data presented herein show consistent and reproducible beneficial effects of omega-3 (n-3) fatty acids on bone metabolism and bone/joint diseases. Polyunsaturated fatty acids modulate eicosanoid biosynthesis in numerous tissues and cell types, alter signal transduction, and influence gene expression. These effects have not been explored in the skeletal system. Future research on n-3 fatty acids in bone biology should focus on the following two aspects. First, the further elucidation of how n-3 fatty acids alter biochemical and molecular processes involved in bone modeling and bone cell differentiation, and second, the evaluation of the potential pharmaceutical applications of these nutraceutical fatty acids in maintaining bone mineral status and controlling inflammatory bone/joint diseases.

Eriksen W, Sandvik L, Bruusgaard D. Does dietary supplementation of cod liver oil mitigate musculoskeletal pain? Eur J Clin Nutr., 1996;50(10):689-693.

OBJECTIVE: To investigate the relationship between dietary supplementation of cod liver oil and the intensity of pain in people with musculoskeletal pain.

DESIGN: Cross-sectional study.

SETTING: Data from the Norwegian Health Survey 1985.

SUBJECTS: All adult respondents who had reported musculoskeletal pain (n = 4490).

MAIN OUTCOME MEASURES: Intensity of musculoskeletal pain as assessed by self reports during an interview.

RESULTS: In logistic regression analyses (adjusting for age, gender, socioeconomic status, civil status, smoking habits, physical exercise, mental distress, and use of medicines), there was a negative association between regular intake of cod liver oil during the previous week and intense pain (OR = 0.75; 95% CI: 0.56-1.00; P = 0.048) and considerable/intense pain (OR = 0.81; 95% CI: 0.67-1.00; P = 0.045).

The association was stronger in the 33% of the respondents who reported a musculoskeletal disease, as expressed by the relationship of cod liver oil to intense pain (OR = 0.64; 95% CI: 0.43-0.95; P = 0.028) and considerable/intense pain (OR = 0.74; 95% CI: 0.54-1.03; P = 0.076).

The association varied between diagnostic groups, and was not seen in people who did not report a musculoskeletal disease.

CONCLUSION: The study suggests that people with musculoskeletal pain experience less pain if they take cod liver oil.

Zampelas A, Panagiotakos DB, et al. Fish Consumption Among Healthy Adults Is Associated With Decreased Levels of Inflammatory Markers Related to Cardiovascular Disease. J Am Coll Cardiol, 2005;46:120-124

OBJECTIVES: The aim of this work was to investigate the association between fish consumption and levels of various inflammatory markers among adults without any evidence of cardiovascular disease.

BACKGROUND: Fish consumption has been associated with reduced risk of coronary heart disease, but the mechanisms have not been well understood or appreciated.

METHODS: The ATTICA study is a cross-sectional survey that enrolled 1,514 men (age 18 to 87 years) and 1,528 women (age 18 to 89 years) from the Attica region, Greece. Of them, 5% of men and 3% of women were excluded due to a history of cardiovascular disease.
Among others, C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, serum amyloid A (SAA), and white blood cells (WBC) were measured, and dietary habits (including fish consumption) were evaluated using a validated food frequency questionnaire.

RESULTS: A total of 88% of men and 91% of women reported fish consumption at least once a month. Compared to non-fish consumers, those who consumed >300 g of fish per week had on average 33% lower CRP, 33% lower IL-6, 21% lower TNF-alpha, 28% lower SAA levels, and 4% lower WBC counts (all p < 0.05).
Significant results were also observed when lower quantities (150 to 300 g/week) of fish were consumed. All associations remained significant after various adjustments were made.

CONCLUSIONS: Fish consumption was independently associated with lower inflammatory markers levels, among healthy adults.
The strength and consistency of this finding has implications for public health and should be explored further.

Bhattacharya A, Rahman M, et al. Inhibition of Osteoporosis in Autoimmune Disease Prone MRL/Mpj-Faslpr Mice by N-3 Fatty Acids. J Am Coll Nut, 2005; 24(3)200-209

Objective: Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease involving the breakdown of cartilage and juxta-articular bone, which is often accompanied by decreased bone mineral density (BMD) and increased risk of fracture.
Anti-inflammatory omega-3 fatty acids may prevent arthritis and bone loss in MRL/lpr mice model of arthritis and in humans.

Methods: In this study, the effect of long term feeding of 10% dietary n-3 (fish oil (FO)) and n-6 (corn oil (CO)) fatty acids begun at 6 weeks of age on bone mineral density (BMD) in different bone regions in an MRL/lpr female mouse model of RA was measured at 6, 9, and 12 months of age by dual energy x-ray absorptiometry (DEXA).

After sacrificing the mice at 12 months of age, antioxidant enzyme activities were measured in spleen, mRNA for receptor activator of NF-B ligand (RANKL) and osteoprotegerin (OPG) was measured by RT-PCR in lymph nodes, and synovitis was measured in leg joints.

Results: At 6, 9 and 12 months of age, BMD was significantly higher (p < 0.05) in distal femur, proximal tibia, and lumbar spine of FO fed mice than those of CO fed mice.
Spleen catalase (CAT) and superoxide dismutase (SOD) activities were also significantly higher (p < 0.01) in FO fed mice than in CO fed mice.

Histology of knee joints revealed mild synovitis in CO fed mice, which was not present in FO fed mice. RT-PCR analysis of lymph nodes revealed decreased RANKL mRNA (p < 0.001) expression and enhanced OPG mRNA expression (p < 0.01) in FO fed mice compared to CO fed mice.

Conclusions: These results suggest beneficial effects of long-term FO feeding in maintaining higher BMD and lower synovitis in this mouse model.
These beneficial effects may be due, in part, to increased activity of antioxidant enzymes, decreased expression of RANKL, and increased expression of OPG in FO fed mice thereby altering the RANKL/OPG ratio.

These significant beneficial effects on BMD suggest that FO may serve as an effective dietary supplement to prevent BMD loss in patients with RA.

Fortin PR, Lew RA, Liang MH, et al. Validation of a meta-analysis: the effects of fish oil in rheumatoid arthritis. J Clin Epidemiol, 1995;48(11):1379-1390.

The purpose of this study was to validate the results of a meta-analysis showing the efficacy of fish oil in rheumatoid arthritis with the results of a re-analysis of the complete primary data set.

A Medline search yielded seven published papers. Three additional trials were found by contacting authorities in the field. Inclusion criteria included (1) a double-blind, placebo-controlled study, (2) use of at least one of seven predetermined outcome measures, (3) results reported for both placebo and treatment groups at baseline and follow-up, (4) randomization, and (5) parallel or cross-over design. Papers were scored for quality.

Demographic and outcomes variables were collected. For the re-analysis of the primary data, the same variables were abstracted for the 395 individual patients randomized.

The meta-analysis demonstrated that dietary fish oil supplementation for 3 months significantly reduced tender joint count (rate difference [RD] [95% CI] = -2.9 [-3.8 to -2.1] [p = 0.001]) and morning stiffness (RD [95% CI] = -25.9 [-44.3 to -7.5] [p < 0.01]) as compared with heterogeneous dietary control oils.
The re-analysis of the primary data confirmed a significant reduction in tender joint count (p = 0.001) and in morning stiffness (p < 0.02) in the parallel analysis that ignored interaction terms.
The analyses that included an interaction term between site and treatment again confirmed a significant reduction in tender joint count. The results for morning stiffness were similar to the meta-analysis, but did not quite reach statistical significance (p = 0.052-0.083). The relative improvements in the other outcome variables did not reach statistical significance.

Use of fish oil improved the number of tender joints and duration of morning stiffness at 3 months as analyzed by both meta- and mega-analysis.

The fuller mega-analysis confirmed the results of the meta-analysis. The advantages of mega-analysis were as follows: (1) the ability to analyze the homogeneity of the patient populations, (2) the ability to make clinically sensible adjustments in the form of the comparison, and (3) the ability to examine subsets of the data.

Press Release

A new study explains how a diet high in oily fish like salmon and mackerel improves inflammatory conditions, particularly in combination with low doses of aspirin. In a study in the March 7 issue of The Journal of Experimental Medicine, Arita and colleagues identify an anti-inflammatory lipid in humans that is derived from an essential fatty acid in fish oil.

Fatty fish contain large amounts of omega-3 fatty acids--diet-derived essential fatty acids known to benefit patients with cardiovascular disease and arthritis. This research group recently identified a new class of aspirin-triggered bioactive lipids, called resolvins, the activity of which may in part explain the beneficial effects of omega-3 fatty acids. Resolvins are made from the omega-3 fatty acids by cellular enzymes and can reduce inflammation in mice. The main bioactive component of this class of lipids was identified in mice and named resolvin E1.

The researchers have now identified this lipid in plasma taken from volunteers given omega-3 fatty acids and aspirin. Human resolvin E1, the authors show, inhibits both the migration of inflammatory cells to sites of inflammation and the turning on of other inflammatory cells.

This study also reveals a potential pitfall of COX-2 inhibitors, drugs designed to block inflammation, which have been shown to have negative cardiovascular side effects. COX-2 is involved in making resolvin E1 and the authors suggest that inhibition of vascular COX-2 by these inhibitors might block the synthesis of resolvin E1, which would eliminate an important anti-inflammatory pathway. The experiment to prove this idea, however, has yet to be done.

Source: http://www.eurekalert.org/pub_releases/2005-03/joem-eof022405.php

Lopez-Garcia E, Schulze M, et al. Consumption of (n-3) Fatty Acids Is Related to Plasma Biomarkers of Inflammation and Endothelial Activation in Women. J. Nutr, 2004; 134:1806-1811

We evaluated the hypothesis that intake of (n-3) fatty acids is inversely associated with biomarkers of inflammation and endothelial activation.

We conducted a cross-sectional study of 727 women from the Nurses Health Study I cohort, aged 43?69 y, apparently healthy at time of a blood draw in 1990. Dietary intake was assessed by a validated FFQ in 1986 and 1990.

C-reactive protein (CRP) levels were 29% lower among those in the highest quintile of total (n-3) fatty acids, compared with the lowest quintile; interleukin-6 (IL-6) levels were 23% lower, E-selectin levels 10% lower, soluble intracellular adhesion molecule (sICAM-1) levels 7% lower, and soluble vascular adhesion molecule (sVCAM-1) levels 8% lower.

The intake of -linolenic acid was inversely related to plasma concentrations of CRP (?= ?0.55, P = 0.02), Il-6 (?= ?0.36, P = 0.01), and E-selectin (?= ?0.24, P = 0.008) after controlling for age, BMI, physical activity, smoking status, alcohol consumption, and intake of linoleic acid (n-6) and saturated fat.

Long-chain (n-3) fatty acids (eicosapentaenoic and docosahexaenoic) were inversely related to sICAM-1 (= 0.11, P = 0.03) and sVCAM-1 (= 0.17, P = 0.003).

Total (n-3) fatty acids had an inverse relation with CRP (=0.44, P = 0.007), IL-6 (= 0.26, P = 0.009), E-selectin (= 0.17, P = 0.004), sICAM-1 (= 0.07, P = 0.02), and sVCAM-1 (= 0.10, P = 0.004).

These associations were not modified by intake of vitamin E, dietary fiber, trans fatty acids, or by the use of postmenopausal hormone therapy.

In conclusion, this study suggests that dietary (n-3) fatty acids are associated with levels of these biomarkers reflecting lower levels of inflammation and endothelial activation, which might explain in part the effect of these fatty acids in preventing cardiovascular disease.

Cleland LG, Caughey GE, James MJ, Proudman SM. Reduction of cardiovascular risk factors with longterm fish oil treatment in early rheumatoid arthritis. J Rheumatol,2006;33(10):1973-1979.

OBJECTIVE: Rheumatoid arthritis (RA) is associated with increased risk for cardiovascular (CV) events through multiple factors. Fish oil has been shown to reduce symptoms in RA and to reduce CV risk. We assessed the effect of an antiinflammatory dose of fish oil on CV risk factors within a program of combination chemotherapy for patients with early RA.

METHODS: Patients who chose not to take fish oil (n = 13) were compared with patients who achieved a sustained elevation of eicosapentaenoic acid (EPA) in plasma phospholipid fatty acids (> 5% total fatty acids) while taking fish oil over a 3-year period (n = 18). We examined cellular content of arachidonic acid (AA), synthesis of thromboxane A2 and prostaglandin E2, use of nonsteroidal antiinflammatory drugs (NSAID), traditional CV lipid risk factors, and disease activity at 3 years.

RESULTS: At 3 years, AA (as a proportion of AA plus long-chain n-3 fatty acids that can compete with AA for cyclooxygenase metabolism) was 30% lower in platelets and 40% lower in peripheral blood mononuclear cells in subjects taking fish oil. Serum thromboxane B2 was 35% lower and lipopolysaccharide-stimulated whole-blood prostaglandin E2 was 41% lower with fish oil ingestion compared to no fish oil. NSAID use was reduced by 75% from baseline with fish oil (p < 0.05) and by 37% without fish oil (NS). Favorable changes in fasting blood lipids were seen with, but not without fish oil. Remission at 3 years was more frequent with fish oil use (72%) compared to no fish oil (31%).

CONCLUSION: Fish oil reduces cardiovascular risk in patients with RA through multiple mechanisms.

Watsonville, CA (April 18, 2005) Nordic Naturals, Inc., a leading supplier of fish oil and essential fatty acid (EFA) supplements, announced today the results of a human trial showing beneficial effects of fish oil on pain, as well as symptom management in people with non-surgical arthritis.

The results of this study, conducted by Joseph Maroon, MD, and Jeff Bost, PAC, at the University of Pittsburgh (PA) were presented today at the American Association of Neurological Surgeons' annual meeting in New Orleans, LA.

Adult patients with non-surgical neck or back pain under physician's care were asked to supplement with two (2) capsules daily of ProEPA?, a concentrated fish oil supplement from Nordic Naturals. Two capsules of ProEPA provide 1200 mg of omega-3 EFAs, of which 900 mg are EPA (eicosapentaenoic acid) and 200 mg are DHA (docosahexaenoic acid).

After supplementing with ProEPA for an average of 75 days, 60% of the respondents reported reduction in both overall pain and joint pain, and 59% discontinued taking prescription pain medications or non-steroidal anti-inflammatory drugs (NSAIDs).

In additional reported results, 80% of the subjects reported being satisfied with the improvement experienced from supplementing with ProEPA, and 88% reported that they would continue to take the supplement. Virtually no side effects were reported, which is noteworthy in light of the recent voluntary withdrawals of two widely prescribed NSAIDs: Vioxx® (10/30/04) and Bextra® (4/07/05).

Dr. Maroon noted that they were gratified "to see such a high percentage of patients who were able to stop taking their prescription NSAIDs after starting the omega-3 EFAs. Patient satisfaction exceeded 80%.

Founded by husband-and-wife team Joar and Michele Opheim, Nordic Naturals, maker of ProEPA, is working to set exacting standards for freshness, purity, and taste in omega EFA supplements. The company offers over 30 different fish oil products and EFA blends, including liquids, capsules, and children's chewables. For more information, please visit www.nordicnaturals.com or call 800.662.2544.

Source: Shari Hindman, Integral Marketing. email: sharilhindman1@comcast.net

Calder PC. Dietary modification of inflammation with lipids. Proc Nutr Soc,2002;61(3):345-358.

The n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in high proportions in oily fish and fish oils.

The n-3 PUFA are structurally and functionally distinct from the n-6 PUFA.

Typically, human inflammatory cells contain high proportions of the n-6 PUFA arachidonic acid and low proportions of n-3 PUFA. The significance of this difference is that arachidonic acid is the precursor of 2-series prostaglandins and 4-series leukotrienes, which are highly-active mediators of inflammation.

Feeding fish oil results in partial replacement of arachidonic acid in inflammatory cell membranes by EPA. This change leads to decreased production of arachidonic acid-derived mediators.

This response alone is a potentially beneficial anti-inflammatory effect of n-3 PUFA.

However, n-3 PUFA have a number of other effects which might occur downstream of altered eicosanoid production or might be independent of this activity.
For example, animal and human studies have shown that dietary fish oil results in suppressed production of pro-inflammatory cytokines and can decrease adhesion molecule expression. These effects occur at the level of altered gene expression. This action might come about through antagonism of the effects of arachidonic acid-derived mediators or through more direct actions on the intracellular signalling pathways which lead to activation of transcription factors such as nuclear factor kappa B (NFB).

Recent studies have shown that n-3 PUFA can down regulate the activity of the nuclear transcription factor NFB. Fish oil feeding has been shown to ameliorate the symptoms in some animal models of chronic inflammatory disease and to protect against the effects of endotoxin and similar inflammatory challenges.

Clinical studies have reported that oral fish oil supplementation has beneficial effects in rheumatoid arthritis and among some patients with asthma, supporting the idea that the n-3 PUFA in fish oil are anti-inflammatory.

There are indications that inclusion of n-3 PUFA in enteral and parenteral formulas might be beneficial to patients in intensive care or post-surgery.

Curtis CL, Rees SG, et al. Effects of n-3 fatty acids on cartilage metabolism. Proc Nutr Soc, 2002;61(3):381-389

Although the clinical benefits of dietary supplementation with n-3 polyunsaturated fatty acids (PUFA) has been recognised for a number of years, the molecular mechanisms by which particular PUFA affect metabolism of cells within the synovial joint tissues are not understood.

This study set out to investigate how n-3 PUFA and other classes of fatty acids affect both degradative and inflammatory aspects of metabolism of articular cartilage chondrocytes using an in vitro model of cartilage degradation.

Using well-established culture models, cartilage explants from normal bovine and human osteoarthritic cartilage were supplemented with either n-3 or n-6 PUFA, and cultures were subsequently treated with interleukin 1 to initiate catabolic processes that mimic cartilage degradation in arthritis.

Results show that supplementation specifically with n-3 PUFA, but not n-6 PUFA, causes a decrease in both degradative and inflammatory aspects of chondrocyte metabolism, whilst having no effect on the normal tissue homeostasis.

Collectively, our data provide evidence supporting dietary supplementation of n-3 PUFA, which in turn may have a beneficial effect of slowing and reducing inflammation in the pathogenesis of degenerative joint diseases in man.

Nordstrom D, Honkanen V, Nasu Y, et al. Alpha-linolenic acid in the treatment of rheumatoid arthritis. A double-blind, placebo-controlled and randomized study: flaxseed vs. safflower seed. Rheumatol Int 1995; 14(6): 231-234.

Abstract: In rheumatoid arthritis various pro-inflammatory metabolites of arachidonic acid (AA), such as leukotriene B4 (LTB4) and prostaglandin E2 (PGE2), contribute to tissue destruction and pain. In contrast to AA, which is an omega-6 fatty acid, the omega-3 fatty acids, after having been liberated from the cell membrane phospholipids, are further converted into the non- or anti-inflammatory eicosanoids LTB5 and PGI3. AA concentration is an important regulatory step in the synthesis of both prostanoids and leukotriens.

Dietary supplementation with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has therefore been used to decrease the ratio of AA to EPA or DHA to obtain beneficial clinical effects.

EPA and DHA are found in animal fat and are quite expensive compared to their precursor alpha-linolenic acid (alpha-LNA) found in flaxseed oil. We, therefore, performed a placebo-controlled trial with alpha-LNA in 22 patients with rheumatoid arthritis, using a linoleic acid preparation as a placebo.

After a 3-month follow-up, the treatment group showed an increased bleeding time, but the clinical, subjective (global assessment, classification of functional status, joint score index, visual analogue scale, pain tenderness score) and laboratory parameters (haemoglobin, erythrocyte sedimentation rate, C-reactive protein) did not show any statistical alterations.

AA, EPA and DHA did not change either in spite of a significant increase in alpha-LNA in the treatment group. Thus, 3-month's supplementation with alpha-LNA did not prove to be beneficial in rheumatoid arthritis.

Treatment of Rheumatoid Arthritis with Omega-3 Fatty Acids

By Morten Bryhn, MD, PhD.

Several well conducted clinical studies have clearly demonstrated the potential for omega-3 fatty acids for treatment of joint pain and stiffness. New data shows that omega-3 fatty acids also reduce cartilage degradation.

Omega-3 fatty acids should be used together with antirheumatic drugs for optimal treatment of rheumatic diseases.

Rheumatoid arthritis (RA) is a chronic disease affecting about 1% of the population, women three times more often than men. About 80% develop the disease between the ages of 35 and 50. Family studies indicate that RA is a hereditary disease. About 79% of people with the genetic code of HLA-DR4 develop RA compared to only 28% of those with other constitutions. However, genetic risk factors cannot fully account for the incidence of RA, suggesting that dietary habits and other environmental factors also play a role in the etiology of the disease. Even if the Japanese population is genetically exposed to the same risk of getting RA as the Western population the prevalence of the disease is much lower (1). Dietary habits may influence the risk of acquiring the disease and may also influence the course and symptoms related to the disease.

Inhabitants of Greenland and the Faroe Islands have less rheumatic problems compared to people in the Nordic region. A cohort study in these two populations revealed that RA occurred with prevalence similar to elsewhere in the World. But the clinical picture and the long-term outcome of the disease were quite different. Patients with an overt clinical picture of RA and a history of 10-30 years were working full time in the fishing industry with exposure to a cold and humid environment. Even more interesting x-ray pictures of their hands showed very little joint deformations. And they had only traces of inflammatory cytokines (IL-1 and TNF) in plasma, laboratory parameters that are constantly elevated in these patients.

The inhabitants of Greenland, the Faroe Islands and the coastal population of Japan have easily access to fish and seafood is accepted as very healthy. In seafood and sea mammals we find the omega-3 fatty acids known to interfere with a series of inflammatory events in the human body protecting against RA and other autoimmune diseases.

The London Medical Journal published the first scientific publication on effects of fish oil against rheumatism in 1783 describing the current practice at Manchester Infirmary. This report was based on positive observations in a disease with no treatment at that time. However, the modern documentation on omega-3 fatty acids in rheumatic disease comprise well designed, controlled studies showing positive effects on symptoms such as pain, morning stiffness and grip strength. A meta-analysis on all these studies has been published (2) and recommendations on dose have been given (3).

The modern basis for treatment of patients with RA constitutes a combination of symptom treatment and prevention of joint deformation. Symptom relief increase quality-of-life but even more important is prevention of joint destruction, which inevitably will lead to reduced function and invalidity. Pharmacological treatment reduces or prevents negative effects of compounds released by the immune system responsible for the disease. Potent pharmaceuticals have been developed which may change the long-term outcome for RA. However, the omega-3 fatty acids from fish oil, EPA and DHA do the same thing as the pharmaceuticals. The mode-of-action may be different and the potency lower but the effects brought about is certainly more natural compared to the drugs. This may explain why treatment with omega-3 capsules is usually well tolerated with no risk of serious side effects. It has also been demonstrated that omega-3 fatty acids reduce the cartilage destructing enzymes responsible for joint destruction (4).

This finding is very important and places omega-3 fatty acids as a natural supplement in combination with anti-rheumatic drugs.

A therapeutic effect on RA utilizing omega-3 fatty acids cannot be achieved by means of increasing the number of fish meals only.

A high-quality omega-3 concentrate in the dose of 3g or more daily should be used. Clinical response will not occur immediately but will start after 2-3 months and may even increase further during chronic use (5). At the same time the intake of red meat (high in AA and saturates) should be restricted (2).

Omega-3 capsules may be used concomitantly with antirheumatic pharmaceuticals, which may increase efficacy or even reduce the risk of gastro-intestinal discomfort, which is a regular problem for so called NSAID drugs (6). For people with only minor or transient joint problems omega-3 fatty acids could be the first choice for self-medication.

References:

1) Shichikawa K et al. Ryumachi. Prevalence of rheumatoid arthritis in the Japanese population 1981;21:35-43.

2) Fortin PR et al. Validation of a meta-analysis: The effects of fish oil in rheumatoid arthritis. J Clin Epidemiol 1995;48(11):1379-90.

3) James MJ and Cleland LG. Dietary n-3 fatty acids and therapy for rheumatoid arthritis. Semin Arthritis Rheum 1997;27:85-97.

4) Curtis CL, Hughes CE, Flannery CR, et al. n-3 fatty acids specifically modulate catabolic factors involved in articular cartilage degradation J Biol Chem 2000;275:721-724.

5) Geusens P et al. Long-term effect of omega-3 fatty acid supplementation in active rheumatoid arthritis. Arhtr & Rheumat 1994;37:824-829.

6) Lau CS et al. Effects of fish oil supplementation on non-steroidal anti-inflammatory drug requirement in patients with mild rheumatoid arthritis - a double-blind placebo controlled study. Br J Rheumatol 1993;32:982-989.

Sundstrom B, Stalnacke K, Hagfors L, Johansson G. Supplementation of omega-3 fatty acids in patients with ankylosing spondylitis. Scand J Rheumatol,2006; 35(5):359-362.

OBJECTIVE: To study the effect of supplementation with omega-3 fatty acids on disease variables and drug consumption in patients with ankylosing spondylitis (AS).

METHODS: Twenty-four patients were randomized to either a low-dose (1.95 g omega-3/day) or a high-dose (4.55 g omega-3/day) supplement. Disease activity, functional impairment, erythrocyte sedimentation rate (ESR), and drug consumption were assessed during visits at baseline and at weeks 7, 14, and 21.

RESULTS: Eighteen patients completed the study, nine patients from each group. The patients in the high-dose group exhibited a significant decrease in disease activity according to the Bath Ankylosing Disease Activity Index (BASDAI; p = 0.038), which was not seen in the low-dose group. Significant differences were not found on drug consumption or in functional capacity in either of the groups. No significant differences were found when comparing the results between the high- and low-dose groups.

CONCLUSION: Omega-3 fatty acids in adequate doses may have the capacity to decrease the disease activity of AS. However, larger and better controlled studies are needed before any further conclusions can be made on the extent of this capacity.

Yates A, Bradley JP, Maroon J, et al. Evaluation of lipid profiles, inflammatory markers and the use of Omega-3 EFA in Professional Football Players. Initiation: 2006

Introduction: The risk of cardiovascular disease becomes significant in males at age 30. Because many professional football players carry a large amount of weight and are required to exert extreme bursts of maximal physical effort, they make up a unique class of individuals that may have a higher risk for adverse cardiac events such as heart attacks and death.

Family heart history, obesity and other diet and lifestyle factor also play a major role. Cardiac risk assessment is critical to ensure the health of these premier athletes.

The Pittsburgh Steelers have undertaken a rigorous health screening program using both conventional physical exams and now state of the art blood test to assess these risks.

This same physical contact often results in painful joints which are often treated with NSAIDs. The recent withdrawal of Vioxx and the concern of serious side effects make long term use of the COX-2 family of NSAIDs a significant risk factor.

For this evaluation we plan to evaluate the use of Omega-3 EFAs for both their cardiovascular protective effect, by reducing vascular inflammation and plaque stabilization and their ability to relieve joint tissue inflammation and the associated pain.

Materials and Methods: The study will recruit a total of 40 players of which 20 will be given 2,800 mg of omega-3 EFA (EPA/DHA) at the start of the pre-season for the duration of the season. The other 20 players will be the control group. Both groups will be asked to complete questionnaires, diary logs, NSAIDs usage and pain assessments. Routine pre-, mid- and post season cardiac risk assessment blood work and history and physical exams data will also be collected and results used for this analysis.

With this pilot analysis of 40 NFL players we hope to assess any potential beneficial affects of omega-3 EFA on both reducing cardiac risk by improved blood inflammation and lipid markers and by quantifying any reduction in NSAIDs use and improved pain scores in the treatment group.

Maroon JC, Bost JW. Omega-3 Fatty acids (fish oil) as an anti-inflammatory: an alternative to nonsteroidal anti-inflammatory drugs for discogenic pain. Surgical Neurology, 2006; 65(4):326-331.

Background:
The use of NSAID medications is a well-established effective therapy for both acute and chronic nonspecific neck and back pain. Extreme complications, including gastric ulcers, bleeding, myocardial infarction, and even deaths, are associated with their use.

An alternative treatment with fewer side effects that also reduces the inflammatory response and thereby reduces pain is believed to be omega-3 EFAs found in fish oil. We report our experience in a neurosurgical practice using fish oil supplements for pain relief.

Methods:
From March to June 2004, 250 patients who had been seen by a neurosurgeon and were found to have nonsurgical neck or back pain were asked to take a total of 1200 mg per day of omega-3 EFAs (eicosapentaenoic acid and decosahexaenoic acid) found in fish oil supplements. A questionnaire was sent approximately 1 month after starting the supplement.

Results:
Of the 250 patients, 125 returned the questionnaire at an average of 75 days on fish oil. Seventy-eight percent were taking 1200 mg and 22% were taking 2400 mg of EFAs. Fifty-nine percent discontinued to take their prescription NSAID medications for pain.

Sixty percent (60%) stated that their overall pain was improved, and 60% stated that their joint pain had improved. Eighty percent (80%) stated they were satisfied with their improvement, and 88% stated they would continue to take the fish oil.

There were no significant side effects reported.

Conclusions:
Our results mirror other controlled studies that compared ibuprofen and omega-3 EFAs demonstrating equivalent effect in reducing arthritic pain.

Omega-3 EFA fish oil supplements appear to be a safer alternative to NSAIDs for treatment of nonsurgical neck or back pain in this selective group.