Omega-3 Studien: Arthritis

Omega-3: Fakten - Therapie und Dosierung

Arthritis: ca. 5g/Tag EPA & DHA (90mg/kg)
In Fachzeitschriften wurden folgende Artikel über Omega-3 publiziert. Die Liste dieser Publikationen wurde im April 2003 kompiliert und erhebt keinen Anspruch auf Vollständigkeit. Quelle: MEDLINE.
Die Daten dienen als Referenz für Ärzte und Therapeuten, damit eine therapeutische Dosis für Arthritis festgelegt werden kann.

Dietary modification of inflammation with lipids.
Calder PC: Institute of Human Nutrition, University of Southampton, Bassett Crescent East, UK
Proc Nutr Soc 2002 Aug 61:345-58
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.

Dietary polyunsaturated fatty acids and inflammatory mediator production.
James MJ: Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia; Gibson RA, Cleland LG
Am J Clin Nutr 2000 Jan 71:343S-8S
Many antiinflammatory pharmaceutical products inhibit the production of certain eicosanoids and cytokines and it is here that possibilities exist for therapies that incorporate n-3 and n-9 dietary fatty acids. The proinflammatory eicosanoids prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) are derived from the n-6 fatty acid arachidonic acid (AA), which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsaturated fatty acid content of the modern Western diet. Flaxseed oil contains the 18-carbon n-3 fatty acid alpha-linolenic acid, which can be converted after ingestion to the 20-carbon n-3 fatty acid eicosapentaenoic acid (EPA). Fish oils contain both 20- and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid. EPA can act as a competitive inhibitor of AA conversion to PGE(2) and LTB(4), and decreased synthesis of one or both of these eicosanoids has been observed after inclusion of flaxseed oil or fish oil in the diet. Analogous to the effect of n-3 fatty acids, inclusion of the 20-carbon n-9 fatty acid eicosatrienoic acid in the diet also results in decreased synthesis of LTB(4). Regarding the proinflammatory ctyokines, tumor necrosis factor alpha and interleukin 1beta, studies of healthy volunteers and rheumatoid arthritis patients have shown < or = 90% inhibition of cytokine production after dietary supplementation with fish oil. Use of flaxseed oil in domestic food preparation also reduced production of these cytokines. Novel antiinflammatory therapies can be developed that take advantage of positive interactions between the dietary fats and existing or newly developed pharmaceutical products.

n-3 polyunsaturated fatty acids inhibit the antigen-presenting function of human monocytes.
Hughes DA: Diet, Health and Consumer Science Division, the Institute of Food Research, Norwich Research Park, Colney, Norwich, Norfolk, NR4 7UA, United Kingdom; Pinder AC
Am J Clin Nutr 2000 Jan 71:357S-60S
Diets rich in n-3 polyunsaturated fatty acids (PUFAs) are associated with suppression of cell-mediated immune responses, but the mechanisms are unclear. We hypothesized that n-3 PUFAs can inhibit the function of human antigen-presenting cells. A prerequisite for this role of blood monocytes is the cell surface expression of major histocompatibility complex (MHC) class II molecules [human leukocyte antigen (HLA)-DR, -DP, and -DQ], aided by the presence of intercellular adhesion molecule-1 (ICAM-1) and leukocyte function associated antigens 1 and 3. We showed previously that the n-3 PUFA eicosapentaenoic acid (EPA) inhibits the expression of HLA-DR on unstimulated human monocytes in vitro, but that docosahexaenoic acid (DHA) enhances its expression. However, both n-3 PUFAs suppress the expression of HLA-DR, HLA-DP, and ICAM-1 on interferon-gamma-activated monocytes. We also established that dietary fish-oil supplementation can inhibit the expression of these surface molecules on circulating human monocytes. We subsequently showed that when EPA and DHA were combined in the same ratio as is commonly found in fish-oil-supplement capsules (3:2), there was no significant effect in vitro on the expression of HLA-DR on unstimulated monocytes, but the expression on activated monocytes remained significantly inhibited. In the same in vitro system, the ability of activated monocytes to present antigen to autologous lymphocytes was significantly reduced after culture with the combined n-3 PUFAs. These findings provide one potential mechanism for the beneficial effect of fish oil in the treatment of rheumatoid arthritis, a disorder associated with elevated expression of MHC class II and adhesion molecules on monocytes present within affected joints.

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n-3 polyunsaturated fatty acids and cytokine production in health and disease.
Calder PC: Division of Human Nutrition, School of Biological Sciences, University of Southampton, UK
Ann Nutr Metab 1997 41:203-34
Arachidonic-acid-derived eicosanoids modulate the production of pro-inflammatory and immunoregulatory cytokines. Overproduction of these cytokines is associated with both septic shock and chronic inflammatory diseases. The n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid, which are found in fish oils, suppress the production of arachidonic-acid-derived eicosanoids and EPA is a substrate for the synthesis of an alternative family of eicosanoids. Thus, dietary fats which are rich in n-3 PUFAs have the potential to alter cytokine production. Animal studies have provided a great deal of evidence that feeding plant or fish oils rich in n-3 PUFAs does alter the ex vivo production of tumour necrosis factor (TNF), interleukin 1 (IL-1), IL-6 and IL-2, but many contradictory observations have been made; it is most likely that the discrepancies in the literature result from differences in the cell types and experimental protocols used. Human studies provide more consistent data: several studies have shown that supplementation of the diet of healthy volunteers results in reduced ex vivo production of IL-1, IL-6, TNF and IL-2 by peripheral blood mononuclear cells. Similar findings have been made in patients with rheumatoid arthritis and multiple sclerosis. Animal studies indicate that dietary fish oil reduces the response to endotoxin and to pro-inflammatory cytokines, resulting in increased survival; such diets have been beneficial in some models of bacterial challenge, chronic inflammation and auto-immunity. These beneficial effects of dietary n-3 PUFAs may be of use as a therapy for acute and chronic inflammation and for disorders which involve an inappropriately activated immune response.

The use of n-3 PUFAs (fish oil) in enteral nutrition.
Gerster H: Vitamin Research Department, F. Hoffmann-La Roche Ltd, Basel, Switzerland
Int J Vitam Nutr Res 1995 65:3-20
Severely ill patients in need of enteral nutrition support must obtain all essential nutrients in at least the amounts recommended for daily intake (RDA) by healthy populations. Until recently essential fatty acids have been entirely omitted from enteral solutions or included only in the form of n-6 PUFAs which are structurally important for cell membranes and play a significant role as precursors (esp. arachidonic acid, AA) of eicosanoids (prostaglandins, thromboxanes, leukotrienes). However, in the absence of n-3 PUFAs, these eicosanoids may produce exaggerated effects in acute stress responses causing immunosuppression, platelet aggregation and excessive or chronic inflammation. n-3 PUFAs act as precursors of complementary eicosanoids which counteract the exaggerated responses of AA-derived eicosanoids. Therefore, n-3 PUFAs should be part of any optimally balanced diet and must be included also in enteral solutions. Since the transformation of the n-3 parent fatty acid, alpha-linolenic acid, to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is slow and unreliable, it is necessary to provide them as preformed nutrients as they occur in fish oil. The British Nutrition Foundation recommends a daily intake of EPA and DHA in amounts corresponding to the intake of 3 to 4 g standardized fish oil. The requirements can also be covered by the weekly consumption of 2 to 3 portions of fatty fish. Preliminary clinical trials have shown certain beneficial effects of fish oil intakes in diseases associated with inflammatory reactions such as rheumatoid arthritis or inflammatory bowel disease, in conditions with impaired immune competence such as burns, post-operative situations and cyclosporine treatment after renal transplants, and in conditions with enhanced platelet aggregation such as after coronary angioplasty. While these findings must be verified in strictly controlled trials, the intake of fish oil n-3 PUFAs in a balanced ratio to n-6 PUFAs can be recommended for all patients including those in need of enteral nutrition support.

n-3 fatty acids and the immune system in autoimmunity.
Ergas D: Department of Internal Medicine B, Kaplan Medical Center, Rehovot, Israel; Eilat E, Mendlovic S, Sthoeger ZM
Isr Med Assoc J 2002 Jan 4:34-8
In short-term studies, both in animals and in humans, fish oil seems to exert anti-inflammatory effects. However, these effects may vanish during long-term treatment. There is a possibility that in autoimmune diseases, supplementation of dietary n-3 fatty acids might lead to a decrease in the number of autoreactive T cells via apoptosis, as demonstrated in (NZBXNZW) F1 lupus mice [40]. Thus, the "fade away" effect might be due to regrowth of pathogenic autoreactive cells. In animal models of autoimmune diseases, diets high in n-3 fatty acids from fish oil increase survival and reduce disease severity in spontaneous autoantibody-mediated disease, while n-6 linoleic acid-rich diets appear to increase disease severity. The situation in human disease is probably more complex. Some of the discrepancy between studies can be attributed to methodologic problems. The effect of fish oil is dose, time and disease-dependent. Since the anti-inflammatory effects depend on the balance between n-3 and n-6 fatty acids, the relative proportion of EPA and DHA and possibly co-treatment with dietary vitamin E, the dose/effect ratio may vary between individuals. Furthermore, some animal studies demonstrating efficacy used very high doses that may be incompatible with human consumption. It seems that fish oil is only mildly effective in acute inflammation. In those chronic inflammatory disorders where it was found to be effective, several weeks are necessary to exhibit results. Yet, this mild anti-inflammatory effect, possibly through downregulation of pro-inflammatory cytokine production, leads to striking therapeutic improvement in critically ill patients. Fish oil supplementation seems advantageous especially in acute and chronic disorders where inappropriate activation of the immune system occurs. Fish oil has only a mild effect on active inflammation of diseases such as rheumatoid arthritis, SLE and Crohn's disease, but it could prevent relapse (in some of the studies). In diseases where the inflammation is mild, such as IgA nephropathy, fish oil may slow or even prevent disease progression. The above could explain the observation in some populations of a decreased incidence of inflammatory and autoimmune diseases [3], since the constant consumption of n-3 fatty acids could suppress any autoreactive (or hyper-reactive) T cells. However, if there is already an existing disease, increased consumption might not be beneficial over a long period. Therefore, the use of n-3 fatty acids can be recommended to the general healthy population, not only to prevent atherosclerosis but possibly also to reduce the risk of autoimmunity.

Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis. Clinical and immunologic effects.
Kremer JM: Department of Medicine, Albany Medical College, NY 12208; Lawrence DA, Jubiz W, DiGiacomo R, Rynes R, Bartholomew LE, Sherman M
Arthritis Rheum 1990 Jun 33:810-20
Forty-nine patients with active rheumatoid arthritis completed a 24-week, prospective, double-blind, randomized study of dietary supplementation with 2 different dosages of fish oil and 1 dosage of olive oil. Clinical evaluations were performed at baseline and every 6 weeks thereafter, and immunologic variables were measured at baseline and after 24 weeks of study. The 3 groups of patients were matched for age, sex, disease severity, and use of disease-modifying antirheumatic drugs (DMARDs). Subjects continued receiving DMARDs and other background medications without change during the study. Twenty patients consumed daily dietary supplements of n3 fatty acids containing 27 mg/kg eicosapentaenoic acid (EPA) and 18 mg/kg docosahexaenoic acid (DHA) (low dose), 17 patients ingested 54 mg/kg EPA and 36 mg/kg DHA (high dose), and 12 patients ingested olive oil capsules containing 6.8 gm of oleic acid. Significant improvements from baseline in the number of tender joints were noted in the low-dose group at week 24 (P = 0.05) and in the high-dose group at week 18 (P = 0.04) and 24 (P = 0.02). Significant decreases from baseline in the number of swollen joints were noted in the low-dose group at weeks 12 (P = 0.003), 18 (P = 0.002), and 24 (P = 0.001) and in the high-dose group at weeks 12 (P = 0.0001), 18 (P = 0.008), and 24 (P = 0.02). A total of 5 of 45 clinical measures were significantly changed from baseline in the olive oil group, 8 of 45 in the low-dose fish oil group, and 21 of 45 in the high-dose fish oil group during the study (P = 0.0002). Neutrophil leukotriene B4 production decreased by 19% from baseline in the low-dose fish oil group (P = 0.0003) and 20% in the high-dose group (P = 0.03), while macrophage interleukin-1 production decreased by 38.5% in the olive oil group (P not significant), 40.6% in the low-dose group (P = 0.06), and 54.7% in the high-dose group (P = 0.0005). Tritiated thymidine incorporation in peripheral blood mononuclear cells after stimulation with concanavalin A increased significantly in all 3 groups after 24 weeks, compared with baseline values. We conclude that the clinical benefits of dietary supplementation with omega-3 fatty acids are more commonly observed in patients consuming higher dosages of fish oil for time intervals that are longer than those previously studied. Dietary supplementation with olive oil is also associated with certain changes in immune function, which require further investigation.

Beneficial effect of eicosapentaenoic and docosahexaenoic acids in the management of systemic lupus erythematosus and its relationship to the cytokine network.
Das UN: Department of Medicine, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, India
Prostaglandins Leukot Essent Fatty Acids 1994 Sep 51:207-13
Systemic lupus erythematosus (SLE) is a chronic inflammatory condition characterised by arthritis, cutaneous rash, vasculitis, and involvement of central nervous system, renal and cardiopulmonary manifestations. Abnormalities in the cytokine network is believed to be involved in the pathobiology of this condition. The n-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can suppress T-cell proliferation and the production of interleukin-1, interleukin-2, and tumor necrosis factor by these cells both in vitro and in vivo. Oral supplementation of EPA and DHA induced prolonged remission of SLE in 10 consecutive patients without any side-effects. These results suggest that n-3 fatty acids, EPA and DHA, are useful in the management of SLE and possibly, other similar collagen vascular diseases.

Stabilization of rat serum proteins following oral administration of fish oil.
Saso L: Department of Pharmacology of Natural Substances and General Physiology, University of Rome La Sapienza, Italy; Valentini G, Mattei E, Panzironi C, Casini ML, Grippa E, Silvestrini B
Arch Pharm Res 1999 Oct 22:485-90
The mechanism of action of fish oil (FO), currently used in different chronic inflammatory conditions such as rheumatoid arthritis (RA), is not completely understood, although it is thought that it could alter the metabolism of endogenous autacoids. In addition, we hypothesized that the known capability of fatty acids (FA) of stabilizing serum albumin and perhaps other proteins, may be of pharmacological relevance considering that it is shared by other anti-rheumatic agents (e.g. nonsteroidal antiinflammatory drugs). Thus, we studied the effect of oral administration of FO and corn oil (CO), a vegetable oil with a different composition, on the stability of rat serum proteins, evaluated by a classical in vitro method based on heat-induced protein denaturation. FO, and, to a lower extent, CO inhibited heat-induced denaturation of rat serum (RS): based on the inhibitory activity (EC50) of the major fatty acids against heat-induced denaturation of RS in vitro, it was possible to speculate that in vivo effects of palmitic acid (C16:0) and eicosapentaenoic acid (EPA, C20:5, n-3) may be more relevant than that of linolenic acid (C18:2). To better investigate this phenomenon, we extracted albumin from the serum of animals treated or not with FO with a one-step affinity chromatography technique, obtaining high purity rat serum albumin preparations (RSA-CTRL and RSA-FO), as judged by SDS-PAGE with Coomassie blue staining. When these RSA preparations were heated at 70 degrees C for 30 min, it was noted that RSA-FO was much more stable than RSA-CTRL, presumably due to higher number of long chain fatty acids (FA) such as palmitic acid or EPA. In conclusion, we provided evidences that oral administration of FO in the rat stabilizes serum albumin, due to an increase in the number of protein bound long chain fatty acids (e.g. palmitic acid and EPA). We speculate that the stabilization of serum albumin and perhaps other proteins could prevent changes of antigenicity due to protein denaturation and glycosylation, which may trigger pathological autoimmune responses, suggesting that this action may be involved in the mode of action of FO in RA and other chronic inflammatory diseases.

Anti-inflammatory properties of docosahexaenoic and eicosapentaenoic acids in phorbol-ester-induced mouse ear inflammation.
Raederstorff D: Department of Vitamin and Nutrition Research, F.Hoffmann-La Roche Ltd, Basel, Switzerland; Pantze M, Bachmann H, Moser U
Int Arch Allergy Immunol 1996 Nov 111:284-90
Laboratory animal models and clinical studies suggest that dietary n-3 fatty acids are beneficial in diseases with an inflammatory component such as rheumatoid arthritis or psoriasis. In the present study we investigated the effect of purified docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on phorbol ester (TPA)-induced acute inflammation. Mice were fed for 6 weeks a diet containing 5% corn oil enriched with either 1% DHA or 1% EPA and compared with a group receiving 6% corn oil only. The dietary treatment with DHA or EPA elevated the n-3 polyunsaturated fatty acids as expected in the spleen and ear phospholipids, associated with a reduction in arachidonic acid levels. The degree of ear inflammation was quantified by measuring the four parameters including (1) edema as the increase in ear biopsy weight, (2) polymorphonuclear cell infiltration as myeloperoxidase activity (MPO) at the site of inflammation, (3) prostaglandin E2 (PGE2) and (4) leukotriene B4 (LTB4) concentrations in ear edema. The addition of DHA to the diet reduced significantly the edema formation and the MPO activity 24 h after TPA challenge. Both DHA and EPA significantly reduced the PGE2 and LTB4 levels compared with animals fed corn oil. This result suggests that DHA rather than EPA may be useful in the adjuvant treatment of diseases where acute inflammatory processes play a role.

The eicosapentaenoic to docosahexaenoic acid ratio of diets affects the pathogenesis of arthritis in Lew/SSN rats.
Volker DH: Discipline of Nutrition & Dietetics, Faculty of Medicine & Health Sciences, University of Newcastle, Callaghan, NSW 2308, Australia; FitzGerald PE, Garg ML
J Nutr 2000 Mar 130:559-65
Dietary-induced changes in tissue levels of polyunsaturated fatty acids modify inflammatory reactions through changes in the synthesis of lipid and peptide mediators of inflammation. Four semipurified 20% fat diets, based on beef tallow (BT), safflower oil (SFO), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were provided. The DHA and EPA ratios of the (n-3) fatty acid-based diets were 1.1 and 3.4, respectively. The effect of prefeeding diets differing in EPA to DHA ratios prior to the induction of streptococcal cell wall (SCW) arthritis in female Lew/SSN rats was examined. Weanling rats were fed diets for 5 wk before arthritis induction and 5 wk post-arthritis induction. Footpad thickness, hock circumference, plasma and macrophage fatty acids and histological assessment were compared. There were no differences in food intake and final body weights among the groups. Footpad inflammation, reported as percentage change (adjusted for growth) was greatest for rats fed the BT-based diet, intermediate in those fed the SFO-based diet and least for the rats fed the EPA- and DHA-based diets (P < 0.05). Macrophage phospholipids revealed cellular incorporation of EPA and DHA from the fish-oil based diets which modified lipid and peptide mediators of inflammation. Histological sections of rat hocks ranked by severity of arthritis-related changes suggested that the SFO- and EPA-based diets were more successful in ameliorating the destructive arthritic phase in hock joints than the BT- and DHA-based diets (P = 0.09) in this model of arthritis. The course of SCW-induced arthritis can be altered by diet-induced changes in macrophage fatty acid composition. The EPA-based diet is more effective in suppression of inflammation than the DHA-based diet.

Pathologic indicators of degradation and inflammation in human osteoarthritic cartilage are abrogated by exposure to n-3 fatty acids.
Curtis CL: Connective Tissue Biology Laboratories, School of Biosciences, Cardiff University, Wales, UK; Rees SG, Little CB, Flannery CR, Hughes CE, Wilson C, Dent CM, Otterness IG, Harwood JL, Caterson B
Arthritis Rheum 2002 Jun 46:1544-53
OBJECTIVE: To determine if n-3 polyunsaturated fatty acid (PUFA) supplementation (versus treatment with n-6 polyunsaturated or other fatty acid supplements) affects the metabolism of osteoarthritic (OA) cartilage. METHODS: The metabolic profile of human OA cartilage was determined at the time of harvest and after 24-hour exposure to n-3 PUFAs or other classes of fatty acids, followed by explant culture for 4 days in the presence or absence of interleukin-1 (IL-1). Parameters measured were glycosaminoglycan release, aggrecanase and matrix metalloproteinase (MMP) activity, and the levels of expression of messenger RNA (mRNA) for mediators of inflammation, aggrecanases, MMPs, and their natural tissue inhibitors (tissue inhibitors of metalloproteinases [TIMPs]). RESULTS: Supplementation with n-3 PUFA (but not other fatty acids) reduced, in a dose-dependent manner, the endogenous and IL-1-induced release of proteoglycan metabolites from articular cartilage explants and specifically abolished endogenous aggrecanase and collagenase proteolytic activity. Similarly, expression of mRNA for ADAMTS-4, MMP-13, and MMP-3 (but not TIMP-1, -2, or -3) was also specifically abolished with n-3 PUFA supplementation. In addition, n-3 PUFA supplementation abolished the expression of mRNA for mediators of inflammation (cyclooxygenase 2, 5-lipoxygenase, 5-lipoxygenase-activating protein, tumor necrosis factor alpha, IL-1alpha, and IL-1beta) without affecting the expression of message for several other proteins involved in normal tissue homeostasis. CONCLUSION: These studies show that the pathologic indicators manifested in human OA cartilage can be significantly altered by exposure of the cartilage to n-3 PUFA, but not to other classes of fatty acids.