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Adkisson, H.D., Tranik,T.M., & Wuthier,R.E.

Relationship of cartilage Mead acid levels to aging and development of osteoarthritis.

The authors studies the relationship of cartilage mead acid levels to aging and development of osteoarthritis. They looked at the fatty acid status of weight-bearing and non-weight bearing cartilage from autopsy specimens, or from surgical procedures, in various ages and disease states. Young cartilage is characterised by the presence of high levels of 20:9 w-9, Mead acid, indicating a relative deficiency of EFA. Skeletal muscle from the same subjects showed normal EFA levels, and no Mead acid. Age decreases the Mead acid level and increases the EFA level, with weight-bearing cartilage having more EFA and less Mead acid than costal tissues. Cartilage from osteoarthritis affected joints showed even lower Mead acid levels and even higher w-6 EFA levels, leading the authors to speculate that accumulation of w-6 EFAs in cartilage might predispose towards the development of OA, and that the presence of Mead acid might somehow be protective. They also speculate that weight-bearing cartilage might be better vascularised than costal tissue.

Poster Presentation at the Third International Conference on Essential Fatty Acids and Eicosanoids, Adelaide, Australia March 1 1992  

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Belch J.J.

Effects of Altering the Dietary Essential Fatty Acids on the Requirements for NSAIDs in Patients with Rheumatoid Arthritis.

16 rheumatoid arthritis patients were given 540mg gamma linolenic acid/day, 15 patients were given 240mg eicosapentaenoic acid and 450 mg GLA/day, and 18 patients were given liquid parrafin as a placebo. The treatments were continued for 12 months, after which there followed a 3 month placebo period. Results showed a significant subjective improvement for both the EPO and the EPO/EPA combination, compared to placebo. In addition, both of the active groups had significantly reduced their intake of non-steroidal anti-inflammatory drugs (NSAIDs), and measures of disease activity did not worsen. After 3 months of placebo treatment those receiving active had relapsed. Reduction in NSAID use was greatest in the EPO/EPA group.

Ann.Rheum.Dis.,0104:;274

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Brusch C.A., & Johnson,R.            

A New Dietary Regimen for Arthritis. Value of Cod Liver Oil on a Fasting Stomach.

 Report of the open use of cod liver oil to treat arthritis patients. 98 patients were studied, each of which went on a special diet mainly involving addition of cod liver oil( amount unspecified, believed to be 20 mls), mixed either with 40 mls of freshly squeezed orange juice, or of cooled milk.The mixture was shaken, and taken either 4-5 hours after the last evening meal, or 1-2 hours before breakfast.Sugar restriction was also practiced. The authors claimed that 92% of patients responded favourably to this regime, within periods of 2-20 weeks.They claim a marked reduction in pain, general improvement in well-being,less swelling,improved mobility, less fatigue and improved skin, hair and nail condition. Biochemical measures( sedimentation rate, blood sugar levels, and a fall in urine alkalinity).

J.Nat.Medical Assocn.,1959, 51;4:265-71.

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Cleland,  L.G.,

Clinical and Biochemical Effects of Dietary Fish Oil Supplements in Rheumatoid Arthritis.

This   paper reports the results of a  double blind trial of fish oil in RA. The investigators gave 18 Maxepa capsules per day for 3 months to 60 RA patients. The Maxepa patients showed a significant drop in the tender joint score, from 13 to 9.5, compared to a drop from 13 to 12 in the placebo(olive oil) group. Grip strength was significantly increased in the Maxepa group, but not in the olive oil group. Biochemical measures showed a reduction in the generation of the inflammatory leukotriene LTB4 in the Maxepa patients compared to the olive oil group.

J.Rheumatol.,1988, 15;1471-5. 

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Curtis, C.L., Hughes,C.E., Caterson,B., et al.,

n-3 fatty acids specifically modulate catabolic factors involved in articular cartilage degradation.

This study describes specific molecular mechanisms by which supplementation, with n-3 fatty acids (i.e. those present in fish oils) can modulate the expression and activity of degradative and inflammatory factors that cause cartilage destruction during arthritis. Our data show that incorporation of n-3 fatty acids (but not other polyunsaturated or saturated fatty acids) into articular cartilage chondrocyte membranes results in a dose-dependent reduction in: (i) the expression and activity of proteoglycan degrading enzymes (aggrecanases) and (ii) the expression of inflammation-inducible cytokines (interleukin (IL)-1 alpha and tumor necrosis factor (TNF)-alpha) and cyclooxygenase (COX-2), but not the constitutively expressed cyclooxygenase COX-1. These findings provide evidence that n-3 fatty acid supplementation can specifically affect regulatory mechanisms involved in chondrocyte gene transcription and thus further advocate a beneficial role for dietary fish oil supplementation in alleviation of several of the physiological parameters that cause and propagate arthritic disease.

Journal of Biological Chemistry,2000:275(2);721-724.

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Das U.N.,

Interaction(s) Between Essential Fatty Acids, Eicosanoids, Cytokines, Growth Factors and Free Radicals - Relevance to New Therapeutic Strategies in Rheumatoid Arthritis and Other Collagen Vascular Diseases.

Eicosanoids, lymphokines, and free radicals are known to participate in the pathogenesis of inflammation. Tumour necrosis factor (TNF), interleukin-1 and 6 (IL-1 and IL-6) and colony stimulating factor -1 (CSF-1) are secreted mainly by activated macrophages, whereas T-cells secrete IL-2, IL-3, IL-4 and interferon-gamma (IFN-gamma). In addition, activated macrophages and lymphocytes can also produce eicosanoids and free radicals which have potent pro-inflammatory actions. Eicosanoids, lymphokines, and free radicals can modulate the immune response, cell proliferation, stimulate collagenase and proteases secretion and induce bone resorption; events which are known to be associated with various collagen vascular diseases. On the other hand transforming growth factor- beta (TGF-beta) produced by synovial tissue, platelets and lymphocytes can inhibit collagenase production, suppress T-cell and NK-cell proliferation and activation and block free radical generation and seems to be of benefit in rheumatoid arthritis. Drugs such as cyclosporine, 1,25, dihydroxycholecalciferol and pentoxyfylline can block lymphokine and TNF production and thus, may inhibit the inflammatory process. Essential fatty acids, the precursors of eicosanoids, are suppressors of T-cell proliferation, IL-1, IL-2 and TNF production and have been shown to be of benefit in rheumatoid arthritis, systemic lupus erythematosus and glomerulonephritis. Thus, the interactions between essential fatty acids, eicosanoids, lymphokines, TGF-beta and free radicals suggest that new therapeutic strategies can be devised to modify the course of collagen vascular diseases.

Prostaglandins Leukotrienes and Essential Fatty Acids,1991 Dec: 44(4);201-210.

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Kremer, J.B., & Bigaouette,J.

Effects of manipulation of dietary fatty acids on clinical manifestations of rheumatoid arthritis.

 37 RA patients took part in a 12 week prospective, double blind study. 17 had a high pufa /low saturated fat diet with added MaxEPA (10g/d). 20 acted as controls,and had a normal diet with less pufa, together with placebo capsules. At 12 weeks the trial group had less morning stiffness, and  fewer tender joints (6.4v9.0). At follow up 4-8 weeks later,the MaxEPA group were significantly worse than the control group for pain and overall condition. The control group was  better for morning stiffness & tender joints on follow up, probably due to resumption of diet.

The Lancet,1985 Jan 26:i, 184-7.

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Kremer, J.M.,

Fish Oil Fatty Acid Supplementation in Active Rheumatoid Arthritis.

40 active RA patients took part in a double blind trial over 14 week periods, with 4 weeks washout between. Dose was 15 capsules /day. Normal drugs were left unchanged. After 14 wks, time to fatigue was significantly increased and number of tender joints was reduced from a mean of 9 to 5.5. Neutrophil LTB4 production was reduced significantly and correlated with tender joint level. Non significant  differences were  also seen in ARA class, patient and physician assessment of pain, walking time and number of swollen joints.

Annals of Internal Medicine, 1987, 50;3:78-85.

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Kremer,  J.M.,

Omega-3 fatty acid supplementation in rheumatoid arthritis: clinical, laboratory and immunological effects.

Somewhat similar to previous papers, but this time supplying EPA/DHA on a mg/kg basis. Patients were randomly assigned to receive either 27mgEPA/18mgDHA/kg bodyweight, or 54/36, or placebo. Supplementation was for 24 weeks. 

LTB4 and 5 levels were monitored, along with some immunological parameters, including interleukin-1 and -2, T and B cell reactivity to mitogen stimulation, and plasma and cellular thiol concentration. Kremer reports dose-dependent clinical improvements in these patients, along with alterations in immunological parameters. 49 patients were involved, and the high dose group showed significant improvements in number of tender joints, morning stiffness, and overall pain assessment.Il-1 production was reduced (this can mediate cartilage breakdown).

Nato Adv.Res.Workshop,Italy, 1988,June 20-23rd,Belgirate;479.

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Kremer, J.M.,

Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis.

Used Pharmacaps ethyl ester product to deliver 27mg/kg  to 20 patients or 54mg/kg of EPA /day for 24 weeks to 17 patients in a prospective double blind randomised trial.10g of olive oil per day was given to 12 control patients. Major findings were significantly fewer tender and  swollen joints and higher grip strength. Pain was reduced, and clinical state improved. There were also biochemical changes in the fish oil treated groups, indicative of less inflammation.

Arthr.& Rheum.,1990, 33;6:810-820.

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Kremer J.M., Lawrence, D.A., Robinson,D.R., Bigaouette, J., et al .     

Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal antiinflammatory drugs: Clinical and immune correlates. 

Objective: To determine the following: 1) whether dietary supplementation with fish oil will allow the discontinuation of non-steroidal anti-inflammatory drugs (NSAlDs) in patients with rheumatoid arthritis (RA); 2) the clinical efficacy of high-dose dietary omega 3 fatty acid fish oil supplementation in RA patients; and 3) the effect of fish oil supplements on the production of multiple cytokines in this population.

 Methods: Sixty-six RA patients entered a double-blind, placebo-controlled, prospective study of fish oil supplementation while taking diclofenac (75 mg twice a day). Patients took either 130 mg/kg/day of omega 3 fatty acids or 9 capsules/day of corn oil.  Placebo (+diclofenac)  was substituted at week 18 or 22, and fish oil supplements were continued for 8 weeks (to week 26 or 30). Serum levels of interleukin-1 beta (IL-1 beta), 1L-2, 1L-6, and IL-8 and tumor necrosis factor alpha were measured by enzyme-linked immunosorbent assay at baseline and during the study. 

Results:  In the group taking fish oil, there were significant decreases from baseline in the mean (+/- SEM) number of tender joints (5.3 +/- 0.835; P < 0.0001), duration of morning stiffness (-67.7 +/ - 23.3 minutes; P = 0.008), physician's and patient's evaluation of global arthritis activity (-0.33 +/- 0.13; P = 0.017 and -0.38 +/- 0.17; P = 0.036, respectively), and physician's evaluation of pain (-0.38 +/- 0.12; P = 0.004).  In patients taking corn oil, no clinical parameters improved from baseline. The decrease in the number of tender joints remained significant 8 weeks after discontinuing diclofenac in patients taking fish oil (-7.8 +/ - 2.6; P = 0.011) and the decrease in the number of tender joints at this time was significant compared with that in patients receiving corn oil (P = 0.043).  IL-1 beta decreased significantly from baseline through weeks 18 and 22 in patients consuming fish oil (-7.7 +/- 3.1; P = 0.026). 

Conclusion: Patients taking dietary supplements of fish oil exhibit improvements in clinical parameters of disease activity from baseline, including the number of tender joints, and these improvements are associated with significant decreases in levels of IL-1 beta from baseline. Some patients who take fish oil are able to discontinue NSAIDs without experiencing a disease flare.

Arthritis and Rheumatism,1995 Aug:38(8);1107-1114.

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Lau, C. S. ,. Morley,K,D., &. Belch,J.J.

Effects of Fish Oil Supplementation on Non-steroidal Anti-Inflammatory Drug Requirements in Patients with Mild Rheumatoid Arthritis- A Double Blind Placebo Controlled Study.  

Found fewer aspirin-type drugs used when patients were on Maxepa fish oil.

British Journal of Rheumatology,1993:32;982-989.

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Lau, C.S., McLaren,M., & Belch,J.J.

Effects of fish oil on plasma fibrinolysis in patients with mild rheumatoid arthritis.

As rheumatoid arthritis (RA) patients have been shown to have impaired plasma fibrinolysis and fish oil has been suggested to be useful for RA, this study investigated the effects of fish oil on fibrinolytic parameters in patients with RA. Forty-five RA patients were randomised to receive either fish oil (1.7 gm eicosapentaenoic acid and 1.1 gm docosahexaenoic acid/day) or placebo treatment for at least 6 months. Plasma levels of fibrinogen, tissue-plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) activity were measured at 3-month intervals. In the fish oil treatment group, plasma levels of fibrinogen and t-PA activity were reduced at 6 months when compared with baseline [fibrinogen: 3.2 (2.85 - 3.53) g/l vs 3.89 (3.56 - 4.22) g/l, mean (95% confidence intervals for mean), p < 0.02; t-PA activity 1.4 (1.01 - 1.78) units/ml vs 1.94 (1.55 - 2.33) units/ml, p < 0.01]. No significant changes in plasma PAl activity were seen during the treatment period in these patients. Placebo treatment did not significantly alter the plasma levels of fibrinogen or t-PA and PAI activity. In conclusion, fish oil supplementation does not appear to produce an improvement in plasma fibrinolysis. Indeed plasma fibrinogen levels and t-PA activity were reduced. This could be due to an effect of fish oil on acute phase protein production. Alternatively, as t-PA is produced on an ''on demand'' basis, its reduction may be related to the lowering of fibrinogen levels following fish oil therapy.

Clinical and Experimental Rheumatology,1995 Jan:13(1);87-90.

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Magaro, M. 

Effect of Fish Oil on Neutrophil Chemiluminescence Induced by Different Stimuli in Patients with Rheumatoid Arthritis.

Lipid composition plays an important part in the structural and metabolic functions of cell membranes. In particular the production of inflammatory mediators such as prostaglandins and leukotrienes is dependent on polyunsaturated fatty acid precursors. Neutrophil leucocytes participate in inflammatory processes by their phagocytic and killing activities which can be monitored by measuring the photon emission (chemiluminescence). Chemiluminescence was measured in a luminol dependent system after stimulation by either particulate (zymosan) or soluble (phorbol myristate acetate) stimulus in a group of 10 patients with rheumatoid arthritis before and 21 and 45 days after treatment with a diet supplemented with eicosapentaenoic and docosahexaenoic acids. Ten patients with rheumatoid arthritis continuing their usual diet were used as control subjects. A progressive reduction of chemiluminescence stimulated by zymosan and phorbol myristate acetate was found in the patients treated with fish oil supplementation. This result correlated well with the reduction in erythrocyte sedimentation rate and an improvement of clinical parameters. The effects of fish oil derived lipids on neutrophil chemiluminescence are probably due to a change of the lipid composition of the cell membrane which is dependent on the esterification of eicosapentaenoic acid and docosahexaenoic acid in cellular membrane phospholipids. The modification of membrane lipid composition seems to interact in a nonspecific way with the metabolic activation of neutrophils during phagocytosis.

Annals of the Rheumatic Diseases,1992 Jul:51(7);877-880.

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Magaro, M.

Influence of Diet with Different Lipid Composition on Neutrophil Chemiluminescence and Disease Activity in Patients with RA. 

12 Rheumatoid arthritis patients were randomly allocated to either a diet high in saturated fats,(P:S ratio 1.33) or to a high pufa diet( P:S ratio 5.0) supplemented with 9 Maxepa capsules per day for 4 weeks. The Maxepa patients showed significantly less morning stiffness and increased grip strength, as well as reduced neutrophil chemiluminescence. Triglyceride levels were not changed by the treatment, neither was cholesterol, haemoglobin or sedimentation rate. The authors comment that in the allocation of patients to the two treatment regimens, those allocated to receive Maxepa were in fact significantly worse to begin with, making the results even more marked.

Ann.Rheum.Dis.,1988, 47; 793-6. 

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Navarro E., Esteve,M., Olive.A., et al.

Abnormal fatty acid pattern in rheumatoid arthritis. A rationale for treatment with marine and botanical lipids.

Objective. To assess the fatty acid pattern in plasma and synovial fluid (SF) in rheumatoid arthritis (RA) and to determine clinical factors related to possible abnormalities. Methods. Thirty-nine patients with RA were included. SF samples were obtained from 9 patients. Disease activity was assessed using the Ritchie Articular Index and erythrocyte sedimentation rate. Fatty acids were assayed with gas liquid chromatography. Results. Decreased levels of eicosapentaenoic acid (p < 0.0001) and total n3 polyunsaturated fatty acids (p < 0.05) were observed in plasma and in joint fluid, respectively. An increase of the substrates of delta-5-desaturase (C20:3n6 and C20:2n6) and decrease of their products (C20:4n6 and C22:4n6) was observed in plasma total lipids and phospholipids. The long chain mono-unsaturated fatty acids (C20:ln9, C22:ln9, C24:ln9) were increased in the joint fluid and in plasma phospholipids. Patients with active disease showed a mild decrease of several saturated fatty acids, n3, and n6 polyunsaturated fatty acids. Minor abnormalities or no changes in fatty acid profile were found related to use of steroids, non-steroidal anti-inflammatory drugs, and gold salts, or malnutrition. Conclusion. The fatty acid pattern found in RA (decreased levels of n3 polyunsaturated fatty acids) may explain the beneficial effect of fish oil. Changes in n6 polyunsaturated fatty acids suggest that delta-5 desaturation is decreased and this might facilitate the anti-inflammatory effect of botanical lipids in RA.

Journal of Rheumatology,2000:27(2);298-303.

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Sperling, R.I.

Effects of Dietary Supplementation with Marine Fish Oil on Leukocyte Lipid Mediator Generation and Function in Rheumatoid Arthritis.

Gave 20g of Maxepa/day for 6 weeks to 12 RA patients. Found a significant fall in leukotriene LTB4 production (by 33%), and small amounts of LTB5, though not enough to compensate for the drop in LTB4. Mean neutrophil chemotaxis to both LTB4 and FMLP increased toward the normal range at the end of 6 weeks. Platelet activating factor (PAF) declined significantly at week 6( by 37%).There was also a significant decline in joint pain index, and in the patients assessment of disease activity. The authors conclude that the evidence for down-regulation of the generation of pro-inflammatory mediators by neutrophils(LTB4) and monocytes (PAF-acether) and the indications of clinical improvement found in this trial warrant a large long term double-blind investigation of the use of fish oil in RA.

Arthritis & Rheumatism,1997: 30(9);988-997.

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Stammers, T., Sibbald,B., & Freeling,P.

Fish Oil in Osteoarthritis.

Although there is a tradition of use of cod liver oil in arthritis, most of the more modern scientific research on this subject has involved rheumatoid arthritis(RA) rather than the more common form of arthritis, osteoarthritis(OA). The emergence of information on the nutritional significance of eicosapentaenoic acid(EPA) has led to a number of scientifically designed studies to explore it's effects. Several well conducted trials have shown that EPA (in the form of the fish oil Maxepa) helps to reduce the inflammation and discomfort of RA, but as yet, none has looked at OA. That has now changed with the publication of a letter in the Lancet reporting the results of a project involving 26 OA patients .They took 10 mls per day of either cod liver oil or an olive oil placebo plus their usual NSAID's daily for 6 months. Every day of each 4th week, the patients assessed their pain and the degree of interference with their everyday activities, on 10cm visual analogue scales. At the end of the 6 month period, the patients on cod liver oil showed less pain and less interference with their normal activities than patient on placebo, though the difference was not statistically significant.

Lancet,1989;ii:503.  

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Stammers, T.,  Sibbald, B., & Freeling,P.

Efficacy of cod liver oil as an adjunct to non- steroidal anti-inflammatory drug treatment in the management of osteoarthritis in general practice.

A double blind, placebo controlled trial was carried out to assess the efficacy of cod liver oil as an adjunct treatment to non- steroidal anti-inflammatory drugs (NSAIDs) in the management of osteoarthritis in general practice. Eighty six patients were given 10 ml of either cod liver oil or olive oil placebo daily as a supplement to their regular NSAID treatment for 24 weeks. Patients were assessed by their general practitioner at four week intervals for joint pain/inflammation, overall interference with activities, and unwanted effects of treatment. Patients recorded on visual analogue scales their daily pain and the extent to which arthritis interfered with everyday activities. There was no significant benefit for the patients taking cod liver oil compared with those taking placebo. The authors speculate that the metabolic effects of the NSAID's may have interfered with the actions of EPA, neutralising  any anti-inflammatory actions it might otherwise have had.

Annals of the Rheumatic Diseases,1992: 51;128-129.

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Tulleken J.E.,

Vitamin E status during dietary fish oil supplementation in rheumatoid arthritis.

The aim of the trial was to determine whether the benefit in RA from fish oil was due to the fish oil or to the vitamin E added to it. Used 28 patients with active RA and gave them 12 capsules of fish oil per day (31 moles% EPA, 22 moles % DHA, supplying 2g of EPA, 1.3g DHA in 6 g of oil) which contained 5 micromoles of alpha-tocopherol per g of oil (12.9 mg). The control group received the same number of capsules containing fish flavoured coconut oil, containing 10mg of vitamin E.

After 3 months the fish group showed significantly fewer tender joints, fewer swollen joints and a lower RAI score. Pain was lower, as was morning stiffness; grip strength was higher. No changes were noted in the coconut oil group, except that their vitamin E status rose, whereas the fish group did not.

Arthritis & Rheumatism,1990, 33(9):1416-19.

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van der Tempel, H.

Effects of fish oil supplementation in rheumatoid arthritis. 

Used 16 patients in a randomised double blind trial of fish oil compared with a coconut oil placebo. After 12 weeks, the fish oil group was better for joint swelling index and duration of early morning stiffness. Overall clinical condition was also better, but not significantly so. Less LTB4 was produced by the fish oil group.

Annals.Rheum.Diseases.,1980;624.

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