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Immune Function: Original Article

Dietary Fish and Fish Oil and the Risk of Rheumatoid Arthritis

Rosell, Magdalenaa; Wesley, Ann-Mariea; Rydin, Karina; Klareskog, Larsb; Alfredsson, Larsa,c the EIRA study group

Author Information
doi: 10.1097/EDE.0b013e3181b5f0ce
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Abstract

Rheumatoid arthritis is a chronic inflammatory disease that affects approximately 0.5%–0.8% of the Scandinavian population.1–3 The prevalence is 2–3 times higher in women than in men. The disease generally requires life-long medical treatment, with possible benefits of dietary interventions or supplements to slow the progression of the disease and reduce the symptoms.4

Both genetic and environmental factors contribute to the development of rheumatoid arthritis.5–11 Diet is among the environmental factors that have received considerable attention. Still, information on specific dietary factors that modify risk is limited. One notable example is the possible influence of intake of oily fish or fish oil supplements, which has been reported to influence the course of established rheumatoid arthritis.4,12

Interest in the effects of oily fish and fish oils stems from their long-chain omega-3 fatty acids. These fatty acids are precursors of anti-inflammatory eicosanoids and thus may affect inflammatory activity.13 Several studies have reported that consumption of fish oil can improve clinical symptoms and delay the progression of established rheumatoid arthritis.4,12 A milder form of rheumatoid arthritis has been reported on the Faroe Islands, which may be related to the high fish consumption in this society.14 However, whether there is an association between the intake of oily fish or fish oil supplements and the risk of developing rheumatoid arthritis is not clear. Few studies have investigated this, and previous studies have been small, with inconclusive results. Two case-control studies,15–17 based on 168 and 324 cases respectively, indicate a protective effect of fish intake. A cohort study18 including 69 incident cases of rheumatoid arthritis reported that the intake of fat fish was associated with reduced risk of developing rheumatoid arthritis, whereas an increased risk was seen with the intake of medium-fat fish. The use of fish oil supplements has increased over time, mainly due to its reported protective effects regarding cardiovascular disease.19 To our knowledge, no study has reported possible effects of these supplements on the risk of developing rheumatoid arthritis.

We have used information from our large population-based case-control study of rheumatoid arthritis, Epidemiological Investigation of Rheumatoid Arthritis (EIRA), to investigate the possible influence of consumption of oily fish and fish oil supplements on the risk of developing rheumatoid arthritis.

METHODS

Study Base

The study population comprised men and women aged 18–70 years living in a defined area in the middle and southern parts of Sweden. Cases and controls in the present study were recruited between May 1996 and December 2005. Detailed description of the study has been reported earlier.8 The study was approved by the ethics committee at the Karolinska Institutet.

Recruitment of Subjects

Newly diagnosed cases were identified and reported to the study by all public rheumatology units in the study area, as well as by almost all of the few privately-run rheumatology units. A case was defined as a person with a first-time diagnosis of rheumatoid arthritis and at least 4 of the following American College of Rheumatology criteria: morning stiffness, arthritis of 3 or more joints, arthritis of hand joints, symmetric arthritis, presence of rheumatic nodules, presence of serum rheumatoid factor, and radiographic changes.20 All cases were examined and diagnosed by a rheumatologist. For each reported case, a control was randomly selected from the same region, matched for age, sex, and residential area, using a national population register that is continuously updated. There were 13 residential areas, each representing a county or a municipality. If a control declined to participate, was not traceable, or reported having rheumatoid arthritis, a new control was selected. When the study first began, some units also reported cases that did not fulfill the criteria, to enable investigations of undifferentiated arthritis. These subjects were eventually excluded from the study. Controls associated with these excluded cases remained in the study.

Data Collection

A questionnaire containing a wide range of questions about environmental exposures was given to the cases shortly after they had been informed about their diagnosis, and was mailed to the controls. The questionnaires were supposed to be answered at home. Trained interviewers (not connected with the rheumatology units) contacted persons who submitted incomplete questionnaires and obtained the missing information, mostly by telephone. Among the cases, 96% participated, as did 82% for the controls, providing 1889 cases and 2145 controls for the analyses.

Assessment of Intake of Oily Fish and Fish Oil Supplements

The questionnaire contained one question relating to fish intake: “How often have you consumed oily fish during the latest 5 years on average? (eg, herring, mackerel, salmon)” with the following answer options “daily,” “once or twice per week,” “once or twice per month,” and “very seldom or never.” Few participants reported daily consumption of oily fish, and so the categories of daily consumption and weekly consumption were combined, resulting in 3 exposure categories for oily fish intake: “1–7 times per week,” “1–3 times per month,” and “Seldom/never.”

Data on intake of fish oil supplements were obtained through 2 questions: “Have you during the latest 5 years regularly taken vitamin supplements for at least one month?” (Yes/No) and “Have you during the last 5 years taken natural remedies for at least one month?” (Yes/No). Participants who answered “yes” were asked to list the supplement or remedy they had taken, and the years it was taken. We examined these lists by hand to identify fish oil supplements. The proportion of reported supplements with unknown or unclear content was less than 4%, and we consider the likelihood to be small that these unknown supplements contained fish oil. Possible errors introduced by this procedure are nondifferential since it was done without the coder knowing the case/control status of the participants.

Supplements were classified into 4 groups: those with no omega-3 fatty acids; those with omega-3 fatty acids in the form of fish oil; those with omega-3 fatty acids in the form of algae; and those with omega-3 fatty acids in the form of plant extracts (eg, linseed). For each rheumatoid arthritis case and matched control(s) an index year was assigned to indicate the year in which the case got their first symptoms of rheumatoid arthritis. Only supplements taken before the index year were considered as exposure because the onset of the disease may affect the participants' use of supplements. Subjects who reported taking supplements with omega-3 fatty acids before the index year were classified as exposed, and subjects who reported they did not take any form of omega-3 fatty acids containing supplements before the index year were classified as unexposed. There were 130 women and 36 men excluded due to missing information on index year, leaving 2732 women and 1146 men for the analyses on supplements. Fewer than 1% of the subjects reported an intake of supplements containing omega-3 fatty acids in the form of algae or plant extracts, and therefore only fish oil supplements were examined in relation to the risk of developing rheumatoid arthritis.

Detection of Rheumatoid Factor and Antibodies to Citrullined Peptides Among Cases

Blood samples were drawn and rheumatoid factor status was determined for all cases (positive or negative) using local standard methodology at the rheumatology units. Also antibodies to citrullinated peptide antigens were determined in blood samples that had been stored in −80°C using standard methodology. The analysis was made with the Immunoscan-RA Mark2 enzyme-linked immunosorbent assay (ELISA) as described previously.21 A level above 25 U/mL was regarded as positive.

Statistical Analysis

We calculated odds ratios (ORs) and their 95% confidence intervals (CIs) for developing rheumatoid arthritis in relation to the intake of oily fish and the intake of fish oil supplements using logistic regression. For the intake of oily fish, we calculated odds ratios for subjects consuming oily fish 1–7 times/week and 1–3 times/month, using the group who seldom or never consumed oily fish as reference. For the intake of fish oil supplements, odds ratios were calculated for subjects who reported a regular consumption of fish oil supplements before the index year compared with subjects who reported they did not take any form of omega-3 fatty acids containing supplements before the index year. Stratified analyses were made with regard to cases, status regarding rheumatoid factor, and antibodies to citrullinated peptide antigens. Men and women were analyzed separately as well as together. Adjustments were made for age, residential area (13 categories), smoking (in 4 categories: “never smoker,” “current smoker,” “ex-smoker,” and “nonregular smoker”) and, in the analyses including all subjects, sex. With regard to potential confounding factors, smoking is the only established life-style risk factor for rheumatoid arthritis. Other factors proposed to affect risk are body mass index (BMI) and alcohol consumption.11,22–24 Because these factors also may covary with fish intake, further adjustments were made for BMI kg/m2 (in 3 categories: <25 kg/m2, 25–29.9 kg/m2, and 30+ kg/m2) and alcohol intake (in 3 categories: no intake, low intake [1–10 drinks/week] and high intake [>10 drinks/week]). We performed matched and unmatched analyses by means of conditional and unconditional logistic regression, respectively. The results produced by the matched and unmatched analyses were similar. We present only results from the unmatched analyses because these generally had higher precision, especially in the subgroup analyses, when cases were stratified according to rheumatoid factor or antibodies to citrullinated peptide antigens status. All analyses were performed using SAS software 9.1.3 (SAS Institute, Cary, NC).

RESULTS

The study sample included 2863 women and 1181 men (Table 1). Median age was 53 years for women and 55 years for men. Among cases with reported information (rheumatoid factor: 99%, and antibodies to citrullinated peptide antigens: 97%), 66% were rheumatoid-factor positive and 61% were antibodies to citrullinated peptide antigens positive. The prevalence of overweight was fairly similar among cases and controls. Smoking was positively associated with rheumatoid arthritis, as previously reported in detail.8 The intake of alcohol was inversely related to rheumatoid arthritis, more clearly in men than in women; the association between alcohol intake and the development of rheumatoid arthritis in this population and in another Scandinavian study has recently been reported.11

TABLE 1
TABLE 1:
Characteristics of the Cases and Controls

The proportion that consumed oily fish at least weekly was somewhat lower among cases than controls, at least among men, whereas the proportion who consumed oily fish seldom or never was higher among cases than controls. The proportion of subjects who reported an intake of fish oil supplements was low (4% or less).

Compared with subjects who never or seldom consumed oily fish, the odds ratio for developing RA among subjects who consumed oily fish 1–7 times/week was 0.8 (95% CI = 0.6–1.0) for women and men together, after adjustment for age, residential area, sex, and smoking (Table 2). We saw no dose-response pattern. Further adjustments for BMI and alcohol intake did not affect the results (data not shown). The strength of the association was similar among women and men. When investigating subsets of rheumatoid arthritis according to rheumatoid factor or antibodies to citrullinated peptide antigens status, no notable change in the results was seen.

TABLE 2
TABLE 2:
Association of Regular Consumption of Oily Fish With Rheumatoid Arthritis (Compared With Subjects Who Never or Seldom Consume Oily Fish), by Sex and by Rheumatoid Factor and Antibodies to Citrullinated Peptide Antigens Status Among the Cases

Fish oil supplements were not associated with rheumatoid arthritis (OR = 1.1 [95% CI: 0.8–1.6]) (Table 3). Further adjustments for BMI and alcohol intake did not affect the results (data not shown). After stratifying the cases for rheumatoid factor and antibodies to citrullinated peptide antigens status, the numbers of exposed subjects were very few and no clear patterns were seen. Men were not analyzed separately because of very low numbers of exposed subjects.

TABLE 3
TABLE 3:
Association of Intake of Fish Oil Supplements With Rheumatoid Arthritis (Compared With Subjects Who Reported no Supplementary Intake of Any Form of Omega-3 Fatty Acids) by Sex and by Rheumatoid Factor and Antibodies to Citrullinated Peptide Antigens Status Among the Cases

DISCUSSION

In this population-based case-control study including more than 4000 participants, we found that regular consumption of oily fish was associated with a modest decreased risk of developing rheumatoid arthritis. No apparent dose-response pattern was seen, and the results were similar when stratifying the cases for rheumatoid factor and antibodies to citrullinated peptide antigens status. There was no association between use of fish oil supplements and rheumatoid arthritis risk; however, the numbers of exposed cases were small.

Few studies have explored the role of diet in the etiology of rheumatologic diseases. We are aware of 3 previous studies on fish intake and rheumatoid arthritis, and their results are inconclusive. In a Greek study including 168 cases and 137 controls, an inverse association between the intake of olive oil and the risk of developing rheumatoid arthritis was reported.15,16 In an American case-control study including 324 cases and 1245 controls, reported odds ratios were 0.8 (95% CI = 0.5–1.1) for 1 serving/week of broiled or baked fish and 0.6 (0.4–0.9) for ≥2 servings/week; the results became stronger when the analyses were restricted to cases positive for rheumatoid factor.17 No associations were seen with other types of fish. Finally, in a recent Danish cohort study, 69 incident cases were identified during a 5-year follow-up of more than 57,000 persons. The consumption of lean and fat fish was associated with a protective effect (OR = 0.8 [95% CI = 0.5–1.5] and 0.6 [0.3–1.2], respectively) but consumption of medium-fat fish was associated with an increased risk of rheumatoid arthritis (2.1 [1.0–4.3]).18 Other prospective data related to diet and rheumatoid arthritis include the Iowa Women's Health Study on vitamin D and rheumatoid arthritis25 and 3 reports from the EPIC-Norfolk study on fruits, vegetables, antioxidants, and other foods and inflammatory polyarthritis,26–28 but these did not look at the intake of fish or fish oil.

The strengths of this study include its population-based design and the large number of cases. Incident cases of newly diagnosed rheumatoid arthritis, as assessed by a specialist in rheumatology, were identified. All rheumatology units linked to the general welfare system in the study area reported cases, as did most of the few, privately-run rheumatology units. Response rates were high. To reduce the risk of recall bias, only subjects that for the first time received a diagnosis of rheumatoid arthritis were included. The mean duration between the estimated disease onset and inclusion in the study was 10 months. Thus, bias due to change in dietary habits as a result of the disease was likely to be limited.

Recall bias usually relates to the tendency to over-report previous exposure among cases relative to the controls. In our study, the situation is the opposite: cases would have had to systematically understate their previous oily fish consumption relative to controls to explain our findings. Since the categories regarding fish intake were broad (never/seldom; monthly; weekly), and the difference observed was mainly between never/seldom versus monthly or more, it seems unlikely that recall bias explains our findings. The similarity of the findings for monthly and weekly intakes might, on the other hand, be explained to some extent by nondifferential misclassification of oily fish consumption.

We did not find any association between intake of fish oil supplements and rheumatoid arthritis similar to what was seen for oily fish. However, the prevalence of fish oil supplements was low, and the confidence intervals broad. Misclassification of exposure due to misreporting by the participants may occur because of difficulties in recalling dietary habits.29 Dietary habits of occasional nature, such as dietary supplements taken for only short periods of time, might be especially difficult to remember over a 5-year period. Thus, we cannot exclude the possibility that nondifferential misclassification of fish oil supplements may explain their lack of association with risk of rheumatoid arthritis, or that regular consumption over a long period of time may be preventive.

We adjusted for several potential confounding factors, including smoking, BMI, and alcohol intake. A limitation of this study is that we have information on the intake of oily fish through only one question. It was not possible to adjust for other dietary factors such as olive oil or fruits and vegetables, which have been associated with a reduced risk of developing rheumatoid arthritis and may also be related to the intake of fish.30 Hence, the association between oily fish intake and rheumatoid arthritis in the current study may be explained in part by other dietary factors, or by other life-style factors not captured by our questionnaire.

There are plausible mechanisms through which fish oil could protect against the development of rheumatoid arthritis.30 Long-chain fatty polyunsaturated acids are used in the synthesis of eicosanoids, which are central mediators in the inflammatory response. Because the eicosanoids produced from omega-6 fatty acids are pro-inflammatory and those produced from omega-3 fatty acids are more anti-inflammatory, the balance between the 2 fatty-acid families is considered to be important. Supplementation of omega-3 fatty acids has been reported to improve clinical symptoms in people with established rheumatoid arthritis.31 There is weak evidence of positive effects of omega-3 supplementation on other inflammatory diseases such as inflammatory bowel disease and asthma,31 but most of the attention to the omega-3 fatty acids has been in relation to cardiovascular diseases. Both observational and interventional studies have demonstrated a protective effect of omega-3 fatty acids on cardiovascular end-points.32 This has contributed to dietary recommendations in many countries, including Sweden, to encourage a regular consumption of both lean and oily fish.33 Our results on oily fish intake could support a protective effect of omega-3 fatty acids also with regard to rheumatoid arthritis.

In conclusion, we found that intake of oily fish was associated with a modest decreased risk of developing rheumatoid arthritis. No dose-response gradient was observed. Further research is needed to elucidate to what extent an inverse association between consumption of oily fish and risk of rheumatoid arthritis is explained by other covariates (eg, other dietary factors) and by an effect from fish oil itself.

ACKNOWLEDGMENTS

We thank Marie-Louse Serra and Lena Nise for excellent work with the collection of data, Camilla Bengtsson for preparing the dataset, and Henrik Källberg and Lena Nise for help with the analyses. The EIRA study group consists of Eva Baecklund, Akademiska Hospital, Uppsala; Ann Bengtsson and Thomas Skogh, Linköping; Birgitta Nordmark, Johan Bratt, and Ingiäld Hafström, Karolinska University Hospital, Stockholm; Kjell Huddenius, Rheumatology Clinic in Stockholm City, Ido Leden, Kristianstad Hospital; Göran Lindahl, Danderyds Hospital; Bengt Lindell, Kalmar Hospital; Christine Lindström and Gun Sandahl, Sophiahemmet; Björn Lööfström, Katrineholm Hospital; Ingemar Petersson and Annika Teleman, Spenshult Hospital; Christoffer Schaufelberger, Sahlgrenska University Hospital; Patrik Stolt, Västerås Hospital; Berit Sverdrup, Eskilstuna Hospital; Olle Svernell, Västerviks Hospital; Tomas Weitoft, Gävle Hospital.

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