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Background In several studies dietary fish oil has been found to have a beneficial effect on psoriasis, but the results are contradictory and based mainly on open studies or studies of small numbers of patients.
Methods In a four-month double-blind, multicenter trial, we randomly assigned 145 patients with moderate-to-severe psoriasis to receive in their diet either highly purified ethyl esters of n-3 fatty acids ("fish oil"; 6 g of oil per day, containing 5 g of eicosapentaenoic and docosahexaenoic acid) or an isoenergetic amount of corn oil containing mainly n-6 fatty acids. All the patients were advised to reduce their intake of saturated fatty acids. A 48-hour dietary recall was performed, and the fatty-acid pattern in the serum phospholipids was monitored in a subgroup of patients.
Results In the fish-oil group, n-3 fatty acids were increased in serum phospholipids (P<0.001), the ratio of arachidonic acid to eicosapentaenoic acid decreased (P<0.001), and the level of n-6 fatty acids decreased (P<0.001). In the corn-oil group, only docosahexaenoic acid increased significantly (P<0.05). The ratio of polyunsaturated to saturated fatty acids increased in both groups. Plasma concentrations of triacylglycerol decreased from base line in the fish-oil group (P<0.05). The score on the Psoriasis Area and Severity Index, as evaluated by the physicians, did not change significantly during the trial in either group. This was also true of a total subjective score reported by the patients, but a selected area of skin in the corn-oil group showed a significant reduction in the clinical signs (P<0.05). Scaling was reduced from base line in both groups (P<0.01). The fish-oil group had less cellular infiltration (P<0.01), and the corn-oil group had improvement in desquamation and redness (P<0.05). There was no clinically important difference between the two study groups. Among the patients in the fish-oil group, an increase in the concentration of n-3 fatty acids in serum phospholipids was not accompanied by clinical improvement, whereas in the corn-oil group there was a significant correlation between clinical improvement and an increase in eicosapentaenoic acid and total n-3 fatty acids.
Conclusions Dietary supplementation with very-long-chain n-3 fatty acids was no better than corn-oil supplementation in treating psoriasis. Clinical improvement was not correlated with an increase in the concentration of n-3 fatty acids in serum phospholipids among the patients in the fish-oil group, whereas there was a significant correlation between clinical improvement and an increase in eicosapentaenoic acid and total n-3 fatty acids in the corn-oil group.
Eskimos, as compared with Danes, have a low incidence of psoriasis. Eskimos have a high intake of very-long-chain n-3 fatty acids (especially eicosapentaenoic acid and docosahexaenoic acid), found mainly in seal and fish oils, whereas Danes have a high intake of n-6 fatty acids (especially linoleic acid), obtained mainly from vegetable sources and animal fat13,14. The first double bond in n-3 fatty acids is the third carbon position from the methyl end. Both n-3 and n-6 polyunsaturated fatty acids are essential, and one cannot be converted to the other15. Dietary linoleic acid is converted to arachidonic acid, which is metabolized through the lipoxygenase and cyclooxygenase pathways to potent inflammatory derivatives16,17,18. The levels of some of these products are markedly increased in psoriatic plaques, and they may be involved in the pathogenesis of psoriasis through their chemotactic and proliferative effect in human skin19,20. When dietary n-3 fatty acids are consumed, they are incorporated into cell membranes and compete with n-6 fatty acids as substrates for the cyclooxygenase and lipoxygenase pathways21. Eicosanoids from fatty acids of the n-3 series are generally less potent than metabolites from the n-6 series, and the inflammatory reaction is therefore smaller22,23.
Psoriasis is characterized by the infiltration of T cells and macrophages into the dermis. It has been hypothesized that psoriatic lesions erupt when an epidermal influx of antigen-presenting cells and helper T lymphocytes overrides the normal epidermal suppressor mechanism24,25,26. Very-long-chain polyunsaturated fatty acids have an antiproliferative effect on T cells in vitro27. Fish oil might therefore alter immune reactivity and promote a reduction in the expression of psoriasis. On the basis of these observations, we undertook a double-blind, randomized, placebo-controlled study among 145 patients with plaque psoriasis.
Methods
Subjects and Study Design
One hundred forty-five patients with stable plaque psoriasis involving more than 8 percent of the body surface were recruited at five university dermatology clinics (each clinic provided 25 to 34 patients). The patients entered a four-month double-blind, blocked-randomization trial (eight patients per block), undertaken in the winter to exclude the effects of sunshine. The study was approved by the regional board of research ethics, and each patient gave informed written consent. The patients were randomly assigned to either the fish-oil group, in which each patient received six capsules daily, each containing 1 g of highly concentrated ethyl esters of very-long-chain n-3 fatty acids (K85, Pronova A.S., Oslo; 51 percent eicosapentaenoic acid ethyl ester 20:5 n-3, and 32 percent docosahexaenoic acid ethyl ester 22:6 n-3), or to the control group, in which each patient received six capsules of corn oil daily, each containing 1 g (26 percent oleic acid 18:1 n-9, and 56 percent linoleic acid 18:2 n-6). Each capsule also contained 3.6 IU of alpha-tocopherol as an antioxidant28. The patients were examined before the trial and every month thereafter by the same physician. Erythema, infiltration, desquamation, and the area of skin involved were scored separately for the head, trunk, arms, and legs, and these scores were multiplied by the corresponding percentage of the area of the total body (e.g., 10 percent for the head) and summed to produce a score on the Psoriasis Area and Severity Index29. A selected 10-cm2 area representing a plaque with moderate-to-severe involvement was evaluated separately for erythema, infiltration, and scaling according to a four-point scale. On a similar scale, the patients subjectively scored the degree of redness, scaling, and itching and the general effects of the disease on daily living. Ten patients in the fish-oil group and 11 in the corn-oil group later withdrew from the study because of the demands placed on the participants, clinical exacerbations requiring treatment with anti-immune drugs or ultraviolet radiation, a move to another area, or the inability to swallow the study capsules. Sixty-two patients in each group, a total of 44 women and 80 men (mean age, 47 years; range, 19 to 74), completed the trial.
None of the patients received any systemic treatment that could influence their clinical state during the trial or in the four weeks before supplementation began. During the study and in the two weeks before it the only treatment allowed was an emollient cream or hydrocorticosteroid cream used under the close supervision of a dermatologist. Compliance was evaluated by counting the capsules consumed in each period and measuring the fatty-acid composition of serum phospholipids before and after the study.
Dietary Monitoring
The patients were advised to decrease their intake of saturated fatty acids by reducing their consumption of whole-fat milk products, hard margarine, and meat10. Both verbal and written information was given about foods containing high concentrations of saturated fatty acids. Nutritionists estimated the dietary intake of fatty acids before and after the trial in a subgroup of randomly selected patients, using 48-hour dietary recall.
Laboratory Assessment
Samples of venous blood were obtained from the patients before and after dietary supplementation for the measurement of serum cholesterol (49 patients in each group), fasting triacylglycerol (33 in the fish-oil group and 30 in the corn-oil group), and the fatty-acid pattern of phospholipids (36 in each group). The fatty-acid pattern was analyzed by gas-liquid chromatography30. Base-line laboratory measurements included the erythrocyte sedimentation rate, hemoglobin level, white-cell count, serum creatinine level, serum alanine aminotransferase level, and serum 
-glutamyl transpeptidase level.
Statistical Analysis
To test for changes within groups and differences between groups, one-sample and two-sample t-tests were used as appropriate. Pearson's product-moment correlation analysis was used for comparisons.
Results
Dietary and Laboratory Evaluation
Compliance with the protocol regarding the use of dietary oil supplements was good, as evaluated by a capsule count and the measurement of fatty acids in serum phospholipids. According to the data obtained by 48-hour dietary recall, the participants in both groups increased their intake of polyunsaturated fatty acids. The intake of saturated fatty acids, however, was unchanged in both groups (Table 1).
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-linolenic acid (20:3 n-6), and linoleic acid (18:2 n-6) in serum phospholipids. The level of arachidonic acid (20:4 n-6) was unchanged. Dietary supplementation with fish oil promoted a decrease in the ratio of arachidonic acid to eicosapentaenoic acid from 5.0 to 1.1 (P<0.001), whereas the ratio of n-6 to n-3 was reduced from 3.8 to 1.5 (P<0.001). Furthermore, the ratio of polyunsaturated to saturated fatty acids in serum phospholipids was increased from 0.85 to 0.97 (P<0.001), because the increase in total n-3 fatty acids in the fish-oil group was not fully compensated for by a reduction in n-6 fatty acids (Table 2). In the corn-oil group there was a significant increase in docosahexaenoic acid (P<0.05), and the ratio of polyunsaturated to saturated fatty acids increased from 0.87 to 0.95 (P<0.01). There was no correlation between clinical response and the increase in the level of eicosapentaenoic acid (r = 0.069) or docosahexaenoic acid (r = 0.021) in serum phospholipids in the fish-oil group (Table 3). In the corn-oil group, however, there was a significant correlation between clinical improvement (a decrease in the clinical score) and increases in eicosapentaenoic acid (r = -0.34, P<0.05) and total n-3 fatty acids (r = -0.36, P<0.05) (Table 3).
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The erythrocyte sedimentation rates, white-cell counts, hemoglobin levels, and serum creatinine levels were similar in the two groups before treatment; the serum alanine aminotransferase level was 36 percent (P<0.05) higher in the corn-oil group (48 patients) than in the fish-oil group (49 patients) (data not shown).
Clinical Evaluation
Each patient's overall clinical condition was assessed by a physician using the Psoriasis Area and Severity Index. The scores on the index ranged from 3.3 to 39, with a mean of 11 for all the patients, before the trial started. There was no significant difference between groups before supplementation began, with mean (±SE) scores of 10.7 ±0.6 in the fish-oil group and 12.3 ±0.9 in the corn-oil group. No significant changes in the scores were observed in either group after one, two, three, and four months (Figure 1).
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This double-blind, multicenter study included four to five times more patients than any previous study of psoriasis. We found that, as monotherapy, dietary supplementation with fish oil did not improve the patients' total clinical condition and symptoms significantly more than supplementation with corn oil. The concentrations of eicosapentaenoic and docosahexaenoic acid, as well as the ratio of eicosapentaenoic to arachidonic acid, increased significantly in serum phospholipids in the patients receiving fish-oil capsules, confirming satisfactory compliance. Only in the corn-oil group was there a significant correlation of n-3 fatty acids with clinical improvement (Table 3). In patients with psoriasis it is possible that a small increase in the dietary intake of n-3 fatty acids may be of clinical importance. In a double-blind study, fish oil, as compared with placebo, had a beneficial effect on psoriasis8. However, our study lasted longer, the patients received markedly higher doses of eicosapentaenoic and docosahexaenoic acids, and we used corn oil rather than olive oil as a control. If n-3 and n-6 fatty acids do in fact reduce the clinical expression of psoriasis,8 the use of olive oil as a control might indicate that fish oil had a beneficial effect. However, this possibility was not supported by Bjorneboe et al.,12 whose double-blind, randomized clinical trial found no beneficial effect of either n-3 fatty acids or olive oil on psoriasis.
Corn oil contains mainly linoleic acid, which may be converted into longer-chain n-6 fatty acids such as dihomo-linolenic and arachidonic acid. Both linoleic and arachidonic acid may inhibit the proliferation of T cells cocultured with epidermal antigen-presenting cells, whereas oleic acid does not have such an effect27. Since psoriasis is characterized by the involvement of activated T cells, corn oil as well as fish oil may exert a beneficial effect on this part of the immune response. This could explain why we found no difference between the fish-oil and corn-oil groups. It should be noted, however, that the fatty-acid pattern of corn oil is similar to the fatty-acid pattern in the Western diet, and corn oil might thus have little influence on the fatty-acid pattern of serum phospholipids (Table 2). This does not exclude the possibility that corn oil might influence the fatty-acid pattern of epidermis and dermis.
Since our study was performed in the winter, we would expect the clinical signs of psoriasis to worsen, because people were less exposed to ultraviolet B radiation. In a controlled study, Gupta et al.31 found a beneficial effect of dietary supplementation with fish oil combined with ultraviolet B treatment. Ultraviolet B radiation and docosahexaenoic acid are both reported to have a suppressive effect on antigen-presenting cells in the epidermis,27,32 and a synergistic effect of ultraviolet B radiation and docosahexaenoic acid is thus possible. The suppression of epidermal antigen-presenting cells, which are responsible for T-cell activation in psoriatic lesions,25,27 could therefore reduce the expression of psoriasis.
Free radicals may interact with polyunsaturated fatty acids, causing lipid peroxides, ketones, and aldehydes to form, which may cause cellular damage. Alpha-tocopherol is an important scavenger of free radicals and can thereby reduce lipid peroxidation33,34. In previous studies among patients with psoriasis12 and atopic dermatitis,30 the level of serum alpha-tocopherol was significantly reduced in the fish-oil groups, whereas in the control groups receiving olive oil it was not. Furthermore, there was a negative correlation between clinical improvement and a decrease in the serum concentration of alpha-tocopherol30. This suggests that a reduction in serum alpha-tocopherol levels may partially counteract the beneficial effects of n-3 fatty acids. We did not measure the serum concentration of alpha-tocopherol in our study, but in another group of 156 patients with moderate hypertension, Bonaa et al.35 demonstrated that the same dose of an identical fish-oil concentrate combined with alpha-tocopherol did not significantly alter the serum concentration of alpha-tocopherol. Thus, a reduction in serum alpha-tocopherol levels is probably not responsible for the lack of clinical response to n-3 fatty acids in our study.
In this study we demonstrated that dietary supplementation with capsules containing highly concentrated fish oil results in a significant increase in the ratio of eicosapentaenoic to arachidonic acid in serum phospholipids and an increase in the ratio of polyunsaturated to saturated fatty acids. However, these changes did not improve the clinical state of patients with stable psoriasis any more than did dietary supplementation with corn oil. The possibility that fish oil may potentiate the effects of other antipsoriatic treatments, such as ultraviolet B radiation, cannot be excluded, however.
Supported by grants from the Norwegian Cancer Society, Pronova A.S., Odd Fellow Medisinske Vitenskapelige Forskningsfond, Nordisk Insulinfond, Freia Chocolade Fabriks Medicinske Fond, and Arne Ingels legat. Dr. Soyland is a research fellow of the Norwegian Cancer Society.
We are indebted to Pronova A.S. for providing the K85 and corn-oil capsules.
Source Information
From the Institute for Nutrition Research, University of Oslo, Oslo (E.S., K.S., G.E.A.B., C.A.D.); Department of Dermatology, Rikshospitalet and University of Oslo, Oslo (J.F., G.R.); Department of Dermatology, Ulleval Hospital and University of Oslo, Oslo (M.S., P.T.); Department of Dermatology, Haukeland Hospital and University of Bergen, Bergen (L.R., S.H.); Department of Dermatology, Regional Hospital and University of Trondheim, Trondheim (K.M.); and Department of Dermatology, Regional Hospital and University of Tromso, Tromso (S.O., E.S.F.) -- all in Norway.
Address reprint requests to Dr. Soyland at the Institute for Nutrition Research, University of Oslo, P.O. Box 1046, Blimder, Oslo N-0316, Norway.
References
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