Fat, n-6 and n-3 fatty acid intake in rheumatoid arthritis and osteoarthritis patients

Abstract The aim of this study is to determine the total fat intake and n-6 to n-3 polyunsaturated fatty acid (PUFA) ratio of rheumatic disease patients (considered candidates for n-3 PUFA supplementation) and to describe the likely influence of the background diet on supplementation efficacy. Consecutive patients with a diagnosis of rheumatoid arthritis and osteoarthritis volunteered to participate in a dietary survey. A previously validated semi-quantitative food frequency questionnaire was administered by a dietitian. One hundred and two patients (52 rheumatoid arthritis, 50 osteoarthritis completed the survey. There were no significant dietary differences between the two groups. There was marked inter-subject variability in n-6 intake (2.5 to 43.4 g per day) and n-3 intake (0.6 to 4.7 g per day) and the n-6 to n-3 ratio varied between 2.3 and 12.7 with a mean n-6 to n-3 ratio of 7 to 1. Indication of significant change in dietary fat composition in recent years suggests that background dietary factors must be determined contemporaneously with any intervention. (Aust J Nutr Diet 1998;55:69-73).

Keywords: food frequency questionnaire, rheumatoid arthritis, osteoarthritis, polyunsaturated fatty acids, n-6:n-3 ratio, dietary fat intake.

Introduction
Osteoarthritis and rheumatoid arthritis are the two most common forms of arthritis with a general population prevalence of 1 to 3% in the case of rheumatoid arthritis, and age-related increasing prevalence for osteoarthritis that reaches near universality in those over 70 years of age ( 1, 2). Both diseases have the capacity to cause significant disability and are a major component of health expenditure ( 3).

The primary target of most forms of treatment is control of inflammation, which in rheumatoid arthritis is systemic and recognised to be the principal mechanism of tissue damage. In osteoarthritis, inflammatory changes, though confined to joints and less intense than in rheumatoid arthritis, are nevertheless an important source of pain and a potential factor in the development of joint damage ( 4, 5).

Available treatments are generally held to be unsatisfactory and to have ameliorating effects only, while carrying significant risk of complications. For example, non-steroidal anti-inflammatory drugs, the most commonly used class of drugs, carry a 5 to 25% chance of gastroduodenal ulceration when used in chronic therapy ( 6, 7). Non-steroidal anti-inflammatory drugs exert their effect through inhibition of prostaglandin production by blocking cyclooxygenase, affecting both isoforms of the enzyme in a largely non-selective fashion and thereby accounting for the gastropathic as well as the desired antiphlogistic effects ( 8).

The recognition that dietary polyunsaturated fatty acids (PUFAs) are incorporated into cell wall phospholipids and participate in prostaglandin and leukotriene production, and are involved in modulation of cytokine (interleukins, tumor necrosis factor) production and yield end products of lower phlogistic capacity ( 9, 10), has led several groups to try to gain a therapeutic effect by dietary manipulation with a potential for reduced complication risks. Most of the trials have relied on supplementation with capsules of fish oil, and although doses as high as 6 g per day of n-3 PUFA have been used, only moderate benefits have emerged ( 11). As the effects of n-3 PUFAs are based on the competitive inhibition of the n-6 PUFAs derived 2-series prostanoids and 4-series leukotrienes, the ratio of n-3 to n-6 PUFAs is an important aspect, and failure to control for this in the background diet of subjects offers a potential explanation for the lack of highly significant anti-inflammatory benefits through supplementation ( 1).

A detailed dietary survey was undertaken to determine the extent of variation in dietary fat intake of rheumatoid arthritis and osteoarthritis patients, Rheumatoid arthritis and osteoarthritis patients were surveyed because both provide a model of inflammatory disease with nonsteroidal anti-inflammatory drug use. The relationship between dietary fat intake and inflammatory disease activity may reflect differing levels of fat intake in rheumatoid arthritis and osteoarthritis patients. A comparison of levels of dietary fat intake of rheumatoid arthritis and osteoarthritis patients with the results of a national dietary survey of dietary intake levels could provide an insight into the extent of dietary fat variation in a representative sample of rheumatoid arthritis patients attending a rheumatology referral centre. This information could provide the basis for an improved, controlled intervention trial with dietary n-3 fatty acid supplementation in rheumatoid arthritis patients.

Methods Subjects
The study was approved by the Human Research Ethics Committee of the University of Newcastle and the Hunter Area Research Ethics Committee. Subjects gave their informed consent and were recruited between November 1995 and January 1996 from the Rheumatology Department of The Royal Newcastle Hospital. The rheumatoid arthritis (32 female and 20 male) and osteoarthritis subjects (38 female and 12 male) were recruited consecutively and interviewed as an extension of their regular clinic visit. Height was measured to the nearest 0.5 cm and weight was measured to the nearest 0.5 kg on regularly calibrated scales. Body mass index (BMI) was calculated [weight (kg)/height (m)[sup2]] from these measures. Occupational status was determined by classification as either working, retired or pension (disability or aged). Subjects specified their educational status by indicating whether they had finished schooling at primary, secondary or tertiary level. The ethnic background was categorised as either Australian-born or born elsewhere.

Use of alternative (non-orthodox) remedies
Subjects were invited to nominate the alternative remedies that they had used in the past and/or were currently using; in particular, current use of lipid-based remedies which could contribute to total dietary fat intake.

Food frequency questionnaire
The survey instrument contained questions that related to the usual frequency of intake of 212 food and drink items, dietary and food preparation practices as well as nutritional beliefs and anxieties. The semi-quantitative food frequency questionnaire (FFQ) was a modified version of the questionnaire used in a large food intake study conducted in Western Sydney in 1989 and 1990, which was validated to categorise and rank fat intake of subjects by a comparison study of seven-day weighed food records. This FFQ has been found to be suitable for classifying and ranking subjects according to their total fat intake ( 12). The modification of the FFQ included questions concerning total fat intake, amount used in spreads, food preparation and cooking techniques as well as identification of brands used. Foods were grouped into ten categories in the questionnaire: cereal foods, cakes and biscuits; dairy foods and eggs; meats; take-aways and mixed dishes; chicken, fish and seafood; fresh and frozen vegetables; canned and dried vegetables; fruits; nibbles, spreads, soup and confectionery; and drinks. After each food group, a series of open-ended and multiple choice questions was posed to determine the non-core foods that may be consumed from the various food groups and the methods of cookery used. Subjects were asked to classify their consumption of the foods listed by times eaten per month, week or day with 'rarely' for foods consumed less frequently than once in six weeks and 'never' for foods that had not been eaten in a year. Seasonal variation in fruit and vegetable intake was accommodated by separately classifying summer and winter intakes. The subjects were offered a computer generated dietary analysis of their food intake on completion of the study.

Nutrient analysis
To analyse the data obtained from the FFQs, Diet 1 (Version 3) computer software package was used (Xyris Software, Highgate Hill, Queensland). This package utilised the 1991-92 NUTTAB Australian nutrient database ( 13) with 134 n-6 (linoleic and arachidonic acids) and n-3 values (alpha-linolenic acid), derived from published values ( 14-16) and UK Food Tables ( 17, 18), added to the database. N-6 and n-3 nutrient values were added to the database in vacant nutrient cells according to the specifications of Xyris Software. These values represented the most significant sources of n-6 and n-3 PUFAs in the FFQ. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) values were not calculated separately because the fish intake of the subjects was minimal and individual fresh fish species could not be identified by the subjects. N-3 PUFA content of tinned fish varieties was calculated as total n-3 PUFA. The FFQ analysis was achieved through the development of a food grid in which 212 food items listed in the questionnaire were entered in order of appearance. For each food question, the most appropriate food from the NUTTAB database was chosen and, where necessary, new recipes were developed and added to the database. Standard serving sizes from the Western Sydney FFQ were used ( 19-24).

Statistical analysis
All demographic (age, gender, occupation, educational status and ethnicity), anthropometric (height, weight and BMI), FFQ analysis (nutrients from Diet 1 Version 3) and supplement intake data were entered into STATA (Version 4.0, Stata Corporation, College Station, Texas). Means and standard deviations (SD) were determined and differences in nutrient intakes between groups were analysed using Student's t-tests or analyses of variance (ANOVA) for normally distributed nutrients or by Kruskal-Wallis test if the distributions were extremely skewed. All tests were two-tailed and results were considered significant at P < 0.05.

Results Subjects
One hundred and two (52 rheumatoid arthritis and 50 osteoarthritis) subjects completed the study. The mean (+\- SD) age and BMI for the rheumatoid arthritis group was 59 (+\- 13) years and 27.1 (+\- 7.1) kg/m2; and the osteoarthritis group was 67.5 (+\- 10.35) years and 29.5 (+\- 5.8) kg/m2 respectively. There were no significant differences between the two groups with respect to gender or cultural and socioeconomic characteristics. In the rheumatoid arthritis group, 83% had reached a secondary level of schooling, 17% were still in the workforce with a mean duration of disease of 14.6 years and 86.5% were born in Australia. Of the osteoarthritis group 72% had completed a secondary level of schooling, 22% were still in the workforce (despite the mean age of 67.5 years) with a mean duration of disease of 14 years and 86% were born in Australia. However, rheumatoid arthritis sufferers were much more likely to have, at some stage tried 'alternative' or, non-medically prescribed remedies such as celery seed, New Zealand green lipped mussels and evening primrose oil (Table 1)( 25, 26). The remedies that were being consumed by the subjects at the time of the trial were not lipid-based and as such were not included in the analysis of diets.

Energy sources
The main foods to contribute energy from fat and oil in both groups of subjects were butter, margarine, cooking oils and fats, meats and meat products, cheese, take-away foods and deep fried foods. The significant sources of n-3 rich PUFA were canola oil and seafood. Foods rich in n-6 included sunflower, safflower and peanut oils, nuts and peanut butter. Energy derived from protein, carbohydrate and fat in the diets of rheumatoid arthritis and osteoarthritis patients was not significantly different (data not shown). Fish meals consumed by rheumatoid arthritis and osteoarthritis subjects were four meals per month and six meals per month respectively.

Dietary fat intake
There was individual variation in the fat intake of subjects in both groups, though inter-group differences were not significant (Table 2). Fat as a percentage of total energy intake was high for both the rheumatoid arthritis (39.8%) and the osteoarthritis (37.3%) groups and in excess of the recommended 30% or less. For these arthritic patients, the estimated percentage of total dietary energy provided by fat was 5 to 6% higher than that estimated in a larger national survey ( 27), although no statistical comparisons were performed. There was a high degree of variation in PUFA intake between individuals in both the rheumatoid arthritis and osteoarthritis groups. Forty-one per cent of rheumatoid arthritis and 40% of osteoarthritis patients consumed less than 10 g of n-6 PUFA per day. Thirty-five per cent and 50% of rheumatoid arthritis and osteoarthritis patients respectively consumed 11 to 20 g of n-6 PUFA per day, whereas 25% and 10% of rheumatoid arthritis and osteoarthritis patients respectively consumed in excess of 20 g of n-6 PUFA per day. The intakes of n-6 PUFA and n-3 PUFA ranged from 2.5 to 43.4 g per day and 0.6 to 4.7 g per day respectively. The n-6 to n-3 ratio varied from 2.3 to 12.7 with a mean n-6 to n-3 ratio of 7:1.

Discussion
The results of this study illustrate the extent of dietary variation in the total fat intake and the n-6 to n-3 PUFA ratio in a representative sample of rheumatoid arthritis and osteoarthritis patients attending a rheumatology referral centre. This information was necessary to determine the influence of the background diet on a prospective n-3 PUFA supplementation trial. Patients from this rheumatology referral centre were to be considered candidates for such a trial. The rheumatoid arthritis cohort was compared with the osteoarthritis group. Both groups had the potential to use non-steroidal anti-inflammatory drugs which inhibit the cyclooxygenase enzyme system and the possibility of a relationship between the level of inflammation and fat intake had been considered. Given the similarity in age range and demographics, our findings that there was no statistically significant difference in the mean of total fat intake between the two groups of rheumatoid arthritis and osteoarthritis patients in this study was in agreement with the literature ( 28, 29). A comparison of total dietary fat intakes of rheumatoid arthritis and osteoarthritis subjects with the general population suggests a similar pattern of fat consumption ( 27).

The semi-quantitative food frequency questionnaire used was initially designed to rank subjects according to total fat and percentage of energy from fat. It has not been validated for use with subjects of this age group and inflammatory disease involvement, primarily because validation by weighed food record is particularly difficult for most rheumatoid arthritis subjects. There is potential for error in this method of n-6 and n-3 PUFA assessment of the diets of subjects with rheumatoid arthritis and osteoarthritis. However, it has been used to rank the n-6 to n-3 ratio of subject diets as a means of selecting subjects for further studies where low n-6 to n-3 ratios will be important 1121.

The survey shows a mean n-6 to n-3 PUFA intake of 7:1, which is close to the recommended ratio for societies consuming a Western diet 130,311 and a much more favourable figure than the 30:1 ratio reported a decade ago ( 32). The change in the mean n-6 to n-3 PUFA ratio appears to be due to the inclusion of canola oil and mono-unsaturated spreads and a lower intake of fats containing n-6 PUFA, such as sunflower, safflower and soyabean oils, The intake of certain foods containing mono-unsaturated fatty acids (MUFA) with little n-6 PUFA content such as olive and Sunola oils and mono-unsaturated margarines (although not n-3 PUFA rich), do not alter the n-6 to n-3 ratio of the diet. Whether n-3 PUFAs derived from plant sources differ significantly in their inflammatory effects from the longer chain n-3 PUFAs from marine sources is uncertain, but the relative contribution of the marine and non-marine sources is a further variable that warrants documentation in analysing intervention outcomes ( 33). In this survey non-marine sources of n-3 PUFAs accounted for a major portion of the total n-3 intake as fish-based meals were not popular with this cohort.

In previous studies, the influence of n-3 PUFA supplementation on clinical and biochemical parameters of rheumatoid arthritis patients has been assessed. Large doses of fish oil containing n-3 PUFAs have been used (up to 6 g of n-3 PUFA per day) in some supplementation trials in which the ratios of n-6 to n-3 PUFAs of the background diet have not been reported. Kremer and his associates, over the past ten years ( 34-37) have used increasing amounts of fish oil supplementation ranging from 1,8 g of EPA per day to approximately 6.0 g of EPA and DHA combined per day. Other research groups ( 38-41) have supplemented varying amounts of fish oil with some significant results in clinical parameters, but significant improvements in biochemical parameters were not evident. It is possible that prior knowledge of the n-6 to n-3 ratio in rheumatoid arthritis subjects may produce more significant results in supplementation trials ( 42). Failure to allow for dietary intake of n-6 PUFA may therefore explain some of the outcome inconsistencies in the trials that have relied on n-3 PUFA supplementation alone. In view of the ratio of n-6 to n-3 PUFA established in the diets of these rheumatoid arthritis and osteoarthritis subjects, there is a need to refine the n-3 PUFA supplementation strategy to achieve significant n-3 PUFA modularation of inflammatory responses in rheumatoid arthritis and osteoarthritis.

Conclusion
The competitive inhibition that exists between n-6 and n-3 PUFA needs to be considered when dietary manipulations are used to achieve therapeutic effects in the treatment of rheumatic diseases. The n-6 to n-3 PUFA ratio of the diet can be reduced by the inclusion of canola oil and mono-unsaturated spreads accompanied by a lower intake of fats containing n-6 PUFA, such as sunflower, safflower and soyabean oils. A community-wide strategy to increase the n-3 to n-6 PUFA content of vegetable oils may be a more effective option than increasing fish consumption which is traditionally low in Western cultures.

Discipline of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, University of Newcastle, NSW

D. Volker, BHSc(N&D) Hons, Postgraduate candidate

M. Garg,. PhD, Senior Lecturer

Department of Rheumatology, The Royal Newcastle Hospital, NSW G. Major, MBBS, FRACP, Director of Rheumatology

Correspondence: M.L. Garg, Discipline of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, University of Newcastle, Callaghan, NSW 2308

Table 1. The self-reported frequency of use of alternative
(non-orthodox) remedies(sup (a) in rheumatoid and osteoarthritic
patients

Rheumatoid arthritis Osteoarthritis
(n = 52) % (n = 50) %

Current use 15.4(b) 16.0
Previous use 48.1 8.0
No use 36.5 76.0

Alternative remedies in current use

Celery seed 37.5 Celery seed 75.0
Copper bracelets 25.0 Apple cider vinegar 25.0
Herbal teas 25.0
Epsom salts 12.5

Frequency of alternative remedies used in the past

Celery seed 28.5 Celery seed 31.5
Seatone(c) 26.3 Seatone(6) 31.5
Apple cider vinegar 3.5 Apple cider vinegar 21.0
Cod liver oil 12.2 Cod liver oil 5.5
Copper bracelets 5.2 Copper bracelets 10.5
Acupuncture 7.0
Herbal teas 5.2
Evening primrose oil 5.2
Aloe vera 5.2
Epsom salts 1.7
(a) Non-medically prescribed remedies.

(b) Frequency of use {percentage of those currently using).

(c) TM The value of Seatone to rheumatoid arthritis and osteoarthritis is that it has a mild anti-inflammatory activity. It is an extract prepared from the NZ green-lipped mussel, Perna canaliculus ( 25, 26).

Table 2. Comparison of fat intake as percentage of energy in rheumatoid arthritis and osteoarthritis and Australian mean for 1993 ( 27)

Legend for Chart:

A - Type of fat
B - Rheumatoid arthritis (n = 52) Mean +\= SD(a)
C - Osteoarthritis (n = 50) Mean +\- SD
D - Australian mean 1993, Male
E - Australian mean 1993, Female

A B C D E

Total fat 39.8 +\- 5.7 37.3 +\- 6.2 33.9 32.5
SFA(b) 15.5 +\- 6.3 13.3 +\- 5.6 13.8 13.2
MUFA(c) 13.3 +\- 6.9 12.8 +\- 5.2 11.7 11.2
PUFA(d) 6.9 +\- 3.8 7.1 +\- 3.5 5.7 5.5
n-6 4.9 +\- 3.2 5.1 +\- 0.3 -- --
n-3 0.7 +\- 0.3 0.7 +\- 0.3 -- --
(a) SD, standard deviation.

(b) SFA, saturated fatty acid.

(c) MUFA, mono-unsaturated fatty acid.

(d) PUFA, polyunsaturated fatty acid.

References
1. Altman RD. Criteria for classification of clinical osteoarthritis. J Rheumatol 1991; 18:10-2.

2. Harris ED. Rheumatoid arthritis: pathophysiology and implications for therapy. N Engl J Med 1990;322:1277-9.

3. Pincus T, Wolfe F. Treatment of rheumatoid arthritis: challenges to traditional paradigms. Ann Intern Med 1991; 115:825-7.

4. Trentham DE. New focus on treatment for rheumatoid arthritis. Curt Opin Rheumatol 1993;5:178-83.

5. Goldberg DL, Egan MS, Cohen AS. inflammatory synovitis in degenerative joint disease. J Rheumatol 1982;9:204-9.

6. Graham DY, White RH, Moreland LW. Duodenal and gastric ulcer prevention with musoprostol in arthritis patients taking NSAIDs. Ann Intern Med 1993;119:257-62.

7. Soll AH, Veinsteen WM, Kurata J, McCarty D. Non steroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med 1991;114:307-19.

8. Day RO. Mode of action of non-steroidal anti-inflammatory drugs. Med J Aust 1988;148:195-9.

9. Dyerberg J, Bang H, Stofferson G, Moncanda S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis. Lancet 1978;2:117-9.

10. Blok WL, Katan MB, van der Meer JW. Modulation of inflammation and cytokine production by dietary (n-3) fatty acids. J Nutr 1996;126:1515-33.

11. Volker DH, Garg ML. Dietary n-3 fatty acid supplementation in rheumatoid arthritis--mechanisms, clinical outcomes, controversies and future directions. J Clin Biochem Nutr 1996;20:83-97.

12. Gelissen I, Roberts DCK. Comparison of estimated nutrient intake by two methods: validation of a food frequency questionnaire. J Hum Nutr Diet 1992;5:215-23.

13. Lewis L, English R. NUTTAB 90: nutrient data tables for use in Australia. Canberra: Australian Government Publishing Service, 1990.

14. Sinclair A, Dunstan GA, Naughton JM, Sanigorski AJ, O'Dea K. The lipid content and fatty acid composition of commercial marine and freshwater fish and molluscs from temperate Australian waters. Aust J Nutr Diet 1992;49:77-83.

15. Australian Government Analytical Laboratory. Analysis of NSW fish and shellfish. Sydney: Fish Marketing Authority, 1989.

16. Wills RBH, Greenfield H. Foods from a major fast food chain. Food Technol Aust 1980;32:363-6.

17. Paul AA, Southgate DAT. McCance and Widdowson's the composition of foods. London: Her Majesty's Stationery Office, 1978.

18. Paul AA, Southgate DAT. First supplement to McCance and Widdowson's the composition of foods. London: Her Majesty's Stationery Office, 1980.

19. Cashel K. A guide to the fat and cholesterol content of foods. J Food Nutr 1985;42:23-30.

20. Baghurst KI, Baghurst P. The measurement of usual dietary intake in individuals and groups. Trans Menz Found 1981:3:139-60.

21. Baghurst KI, Record S. A computerised dietary analysis system for use with diet diaries or food frequency questionnaires. Community Health Stud 1988;12:42-54.

22 Baghurst KI. The food frequency technique and its relevance to population surveys in Australia--a commentary. Aust J Nutr Diet 1992;49:101-3.

23. Baghurst KI, Baghurst P, Record S. Demographic and dietary profiles of high and low fat consumers in Australia. J Epidemiol Community Health 1994;48:26-32.

24. Baghurst KI, Crawford D, Worsley A, Record S. The Victorian nutrition survey--intakes and sources of dietary fats and cholesterol in the Victorian population. Med J Aust 1988; 149:12-20.

25. Darlington LG, Ramsey NW. Review of dietary therapy for RA. Br J Rheumatol 1993;32:507-14.

26. Huskisson E, Scott J, Bryans R. Seatone is ineffective in RA. BMJ 1981;282:1358-9.

27. Baghurst KI, Record S, Syrette J, Powis G. Food and nutrition in Australia--does five years make a difference? Results from the CSIRO Australian food and nutrition surveys 1988 and 1993. Adelaide: CSIRO, 1996.

28. Horwath C. Dietary intake studies in elderly people. In: Bourne GE, editor. Impact of nutrition on health and disease. Basel: Karger, 1989:1-70.

29. Horwath C. Food frequency questionnaires: a review. Aust J Nutr Diet 1994;51:71-6.

30. Allman M. The n-3 polyunsaturated fatty acid status of Australians. Aust J Nutr Diet 1994;51:50-1.

31. Holub BJ. Omega-3 fatty acids: candidate nutrients? In: Gussler J, Scherman E, editors. Nutritional essentiality: a changing paradigm. Report of the Twelfth Ross Conference on Medical Research. Columbus, Ohio: Abbott Laboratories, Ross Products Division, 1993:28-32

32. English R, Cashel K, Bennett S, Berzins J, Walters A, Magnus E National dietary survey of adults, 1983. Canberra: Australian Government Publishing Service, 1987.

33. Caughey GE, Mantzioris E, Gibson RA, Cleland LG, James MJ. The effect on human tumor necrosis factor alpha and interleukin 1beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil. Am J Clin Nutr 1996;63:116-22.

34. Kremer JM, Michalek AV, Lininger L, Huych C, Bigaouette J, Timchalk MA, et al. Effects of manipulating dietary fatty acids on clinical manifestations of rheumatoid arthritis. Lancet 1985;1:184-7.

35. Kremer JM, Jubiz W, Michalek A, Rynes RI, Bartholomew LE, Bigaouette J, et al. Fish oil fatty acid supplementation in active arthritis. Ann Intern Med 1987;106:497-503.

36. Kremer JM, Lawrence DA, Jubiz W, Di Giacomo R, Rynes R, Bartholomew LE, et al. Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis: clinical and immunological effects. Arthritis Rheum 1990;33:810-20.

37. Kremer JM, Lawrence DA, Petrillo GF, Litts LL, Mullaly PM, Rynes RI, et al. Effects of high dose fish oil on rheumatoid arthritis after stopping non-steroidal anti inflammatory drugs. Arthritis Rheum 1995;38:1107-14.

38. Sperling R, Weinblatt M, Robin J, Ravalese JI, Hoover R, House F, et al. Effects of dietary supplementation with marine fish oil on leukocyte lipid mediator generation and function in rheumatoid arthritis. Arthritis Rheum 1987;30:988-97.

39. Cleland LG, French J, Betts HW, Murphy G, Elliott M. Clinical and biochemical effects of dietary fish oil supplements in rheumatoid arthritis. J Rheumatol 1988; 15:1471-5.

40. Neilsen GL, Faarvang KL, Thomsen BS, Teglbjaerg KL, Jensen JT, Hansen TM, et al. The effects of dietary supplementation with n-3 polyunsaturated fatty acids in patients with rheumatoid arthritis: a randomised double blind trial. Eur J Clin Invest 1992;22:687-91.

41. Lau CS, Morely KD, Belch JJ. 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;32:982-9.

42. Cleland LG, James JM, Neumann MA, D'Angelo M, Gibson RA. Linoleate inhibits EPA incorporation from dietary fish oil supplements in human subjects. J Clin Nutr 1992;55:395-9.

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Dianne H. Volker; Gabor A. Major and Manohar L. Garg

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