Nutraceuticals NOW — Spring 2002 — Treatment of Rheumatoid Arthritis with Omega-3 Fatty Acids

Morten Bryhn M.D., Ph.D.

Pronova Biocare

Rheumatoid arthritis (RA) affects about 1% of the population in the Western World, however, the clinical course of the disease may be very different. Cold and humid climate conditions normally accentuate symptoms. It was therefore astonishing to find that inhabitants of Greenland and the Faroe Islands had less rheumatic problems than was to be expected. Of course there may be genetic differences since the Greenland Inuits are different in many respects. But the people from the Faroe Islands are certainly Caucasians. A cohort study in these two populations revealed that RA occured with a 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 rheumatoid arthritis and a history of 10-30 years were working full time in the fishing industry. Even more interesting x-ray pictures of their hands showing usures in juxta-articular bones as would be expected in RA but joint deformations were not present. This would indicate a completely different course of the disease compared to elsewhere. Furthermore the patients had only traces of pro-inflammatory cytokines (IL-1 and TNF) in plasma and very high concentrations of soluble cytokine receptors.

Patients in this part of the World with practically unlimmited resources of seafood, have an intake of omega-3 fatty acids FA between 6 and 12 g. The most abundant of the polyunsaturated FA from fish are EPA and DHA. These fatty acids as well as the omega-6 FA arachidonic acid (AA) are mainly located in the phospholipid membranes of human cells such as the lymphocytes which are actively participating in immunologic events. Activation of these cells will cause release of these FA which are acting as enzyme substrate for the production of prostaglandin, leucotriens and other so called eikosanoids. Eicosanoids from the omega-6 series are highly active while those from omega-3 FA have much less potency. Since EPA has a higher affinity for the enzymes mentioned, eicosanoids which are non-active or with a low biologic potency will be produced. AA-derived eicosanoids on the other hand, producing eicosanoids of the 2- and 4- series, increase the immunologic response from lymphocytes leading to enhanced cytokine production (Il-1 and TNF). The low concentrations of these potent markers of inflammation in Inuits is explained by their high intake of EPA.

Furthermore, the integration of EPA but especially DHA leads to a profound change in cell membrane fluidity which will interfere with the activity of cell-bound structures responsible for cell-signal trafficing. Very important for the activation of the cell-mediated immune system are the so called adhesion molecules (ICAM-1 and E-selectin) essential for the recruitement of inflammatory white blood cells. EPA but even more important DHA reduce the presentation of ICAM-1 and E-selectin probably by interaction of transcription at the intracellular level. This is another and probably very important mode-of-action for omega-3 FA in the treatment of RA. No other pharmaceutical treatment available has the same dual mode-of-action as EPA and DHA.

In essence EPA and DHA reduce the inflammatory process by reducing pro-inflammatory substances such as cytokines. At the same time recruitment of inflammatory white blood cells is hindered by reduced production of adhesion mulecules present on cells as well as tissue.

Several controlled studies have convinsingly demonstrated the positive effects of omega-3 FA in RA. Two reviews have been published summing up the data aquired in this field. The most consistent effects have been achieved on pain and morning stiffness, typical symptoms in RA reducing physical capasity and quality-of-life for the patients. The disease modifying effect of omega-3 fatty acids as seen in Inuits and the Pharoe Island RA patients is interesting but needs to be confirmed in long-term studies. A therapeutic effect on RA utilizing omega-3 FA will require high doses which normally cannot be achieved by means of fish intake. A high-quality omega-3 concentrate in the dose of 3g or more daily should be used since clinical effects on lower doses are not well documented. Clinical response will not occur immediately as with NSAIDs but will start after 2-3 months and may even increase further during chronic use. Intake of red meat (high in AA and saturates) and vegetable omega-6 oils should be reduced. An option for reduction of concommitantly used NSAID's has been documented which could save the patients from gastro-intestinal discomfort often occurring during long-term medication. Omega-3 concentrates may be used concomitantly with drugs normally used for treatment of RA. The omega-3 fatty acids EPA and DHA have documented effects on RA used in doses higher than 3g daily. Effects can be expected after 2-3 months and may increase further by time. There is a possibility for reduction of concommitantly used NSAIDs which could be of importance due to frequent adverse effects from this type of drug.

References:

Cleland LG and James MJ. Rheumatoid arthritis and the balance of dietary n-6 and n-3 essential fatty acids. Br J Rheumatol 1997;36:513-515

Sixty RA patients were randomised to groups having 5.2 g EPA/DHA or matching placebo during 12 weeks. 46 patients completed the study, 23 in each group. Seven patients in each group dropped out or were eliminated for non-compliance to the protocol.

There was a significant reduction of tender joint score in the intervention group compared to placebo and a non-significant reduction in pain score. The number of swollen joints and the degree of morning stiffness was unchanged. Grip strength increased significantly in the omega-3 fatty acid treated patients. Morning stiffness was improved significantly in the placebo group. No change was observed after 4 weeks and 8 weeks of treatment.

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

Seven controlled studies met the inclusion criteria for the meta-analysis. The result showed a statistically significant reduction in the number of tender joints as well as morning stiffness compared to placebo controls.

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

Sufficient evidence exists to advocate omega-3 fatty acids for the treatment of RA and at the same time avoid foods that are very rich in n-6 fatty acids.

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

This was a 12-month study examining the clinical effects and the NSAID's reducing effects of 2.6 g EPA/DHA (group 1), 1.3 g EPA/DHA (group 2) and placebo. Of the 90 patients originally enrolled in the study, 60 patients completed the study, 19 of group 1, 21 of group 2 and 20 in the placebo group. 16 were excluded from data analysis because of premature discontinuation of study treatment and another 14 because of poor compliance.

The pain score as assessed by the patient improved in both groups treated with omega-3 fatty acids, the difference, however, not reaching statistical significance. In each treatment group there were significant reductions from baseline for indexes of pain and number of painful joints. Grip strength improved significantly in the group taking 2.6 g of omega-3 fatty acids. Significant improvement in the patient's global assessment was also observed but only in this group of patients.

In the group taking 2.6 g EPA/DHA 47% of the patients had been able to reduce the dosage of NSAID's and DMARD's during the study period of 12 years compared to 29% in the lower dose group and 15% in the placebo group.

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

This was a second long time study with a duration of 12 months where 32 patients were given 2.6 g EPA/DHA and the control group with the same number of patients received placebo. The obective of the study was to determine the NSAID-reducing effects of omega-3 fatty acids. Of 64 patients enrolled in the study nine in the EPA/DHA group and eighteen patients in the placebo group were withdrawn leaving 37 patients for evaluation.

The requirement for NSAID's decreased continuisly during the study in the active treatment group and was reduced to 40.6% of the original dose at study entry. The difference is statistically significant. In the placebo group the corresponding figure was 84.1%, a not significant difference.

Kremer et al. Effects of manipulating dietary fatty acids on clinical manifestations of rheumatoid arthritis. Lancet 1985;326:184-187

52 patients with RA were randomized to treatment with 2.7 g EPA/DHA for 12 weeks or to a control group receiveing matching placebo capsules (parafine oil). All patients were put on a diet high in polyunsaturated fat and low in saturated fat. 38 patients completed the study and were evaluated: 17 patients in the intervention group and 21 in the control group. Four patients in each group terminated the study due to: incompliance with the diet (n=3), worsening of arthritis (n=2), inability to swallow the capsules (n=2) and one due to concomitant treatment of cancer. Further 6 of the intervention group were excluded from analysis because of non-compliance with the medication.

There was a significant difference in morning stiffness between the two groups due to a worsening in the control group. Improvements in the mean number of tender joints was observed in the intervention group, the difference, however, not reaching statistical significance. A significant worsening was observed in the intervention group regarding patient ratings of pain.

Kremer et al. Fish-oil fatty acid supplementation in active rheumatoid arthritis, a double-blinded, controlled crossover study. Ann Intern Med 1987;106:497-503

40 patients with RA were randomised to two groups having 4.5 g EPA/DHA or matching placebo (control) during 14 weeks. After this first period both groups entered a "wash-out" period with no treatment and subsequently the control group received the same active treatment as in the first period and the active treated group received placebo (cross-over design). 33 patients completed the study. 7 patients were excluded due to violation of the study protocol.

There was a significant reduction in the number of tender joints and swollen joints in the intervention group compared with the controls. Morning stiffness and patient assessment of pain and global assessment improved, however, not reaching statistical significance.

Kremer et al. Dietary fish-oil and olive-oil supplementation in patients with rheumatoid arthritis: clinical and immunological effects. Arthritis Rheum 1990;33:810-820

This was a dose-finding study in RA patients comparing the effect of 6.4 g EPA/DHA with 3.2 g and matching placebo during 24 weeks treatment. A total of 64 patients were enrolled in the study.

49 patients completed the study, 17 in the high dose group, 20 in the low dose group and 12 in the placebo group. There was a significant reduction in the number of tender and swollen joints in the active treatment groups compared to the placebo group. Morning stiffnes was significantly reduced in the high-dose group but not in the low-dose group compared to placebo. Patient evaluation of pain improved in the high-dose group but not in the low-dose group. Patient evaluation of overall disease activity was unchanged.

Faarvang KL et al. Fiskeolje og reumatoid artrit ("Fish oil and rheumatoid arthritis").
Ugeskr Læger 1994;156:3495-3498

Fiftyone RA patients were allocated to treatment with 3.6g omega-3 fatty acids (EPAX 5500TG) or matching placebo and treated for 12 weeks. Active treatment reduced morning stiffness, number of tender joints and C-reactive protein significantly compared to the control group. No adverse effects were recorded.

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Spring 2002 Issue — Treatment of Rheumatoid Arthritis with Omega-3 Fatty Acids