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American Journal of Clinical Nutrition, Vol. 82, No. 2, 451-455, August 2005
© 2005 American Society for Clinical Nutrition

ORIGINAL RESEARCH COMMUNICATION

Dietary ß-cryptoxanthin and inflammatory polyarthritis: results from a population-based prospective study1,2,3

Dorothy J Pattison, Deborah PM Symmons, Mark Lunt, Ailsa Welch, Sheila A Bingham, Nicholas E Day and Alan J Silman

1 From the Arthritis Research Campaign Epidemiology Unit, The University of Manchester, Manchester, United Kingdom (DJP, DPMS, ML, and AJS), and the Department of Public Health and Primary Care, the Institute of Public Health, the University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom (AW, SAB, and NED)

2 The Norfolk Arthritis Register (NOAR) is supported by the United Kingdom Arthritis Research Campaign; the EPIC-Norfolk study is supported by Cancer Research United Kingdom and through additional support from the Medical Research Council, the British Heart Foundation, the Ministry of Agriculture Fisheries and Food, the Department of Health, and the Europe Against Cancer Programme of the Commission of the European Communities.

3 Reprints not available. Address correspondence to AJ Silman, the Arthritis Research Campaign Epidemiology Unit, Stopford Building, The University of Manchester, Oxford Road, Manchester, M13 9PT, United Kingdom. E-mail: alan.silman{at}manchester.ac.uk.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Epidemiologic studies suggest that the antioxidant potential of dietary carotenoids may protect against the oxidative damage that can result in inflammation.

Objective: We investigated the hypothesis that some dietary carotenoids are associated with a reduced risk of developing inflammatory polyarthritis (IP).

Design: The European Prospective Investigation of Cancer Incidence (EPIC)-Norfolk study is a population-based, prospective study of >25000 subjects who completed a baseline 7-d diet diary and were followed up to identify new cases of IP, which was defined as synovitis that affected ≥2 joint groups. Dietary carotenoid intakes were computed from the diet diaries of these subjects, and a nested, case-control analysis was undertaken to compare carotenoid intake between case subjects and age- and sex-matched control subjects.

Results: Eighty-eight incident cases of IP that occurred in the population surveyed were ascertained via the Norfolk Arthritis Register. The mean daily intakes of zeaxanthin and ß-cryptoxanthin were 20% and 40% lower, respectively, in the cases than in the 176 controls, but there were no significant differences in the intakes of either lutein or lycopene. Those subjects in the top one-third of intake of zeaxanthin and ß-cryptoxanthin were at a lower risk of developing IP than were subjects in the lowest one-third [odds ratios (95% CI): 0.48 (0.24, 0.94) and 0.51 (0.25, 1.02) for zeaxanthin and ß-cryptoxanthin, respectively]. The association with ß-cryptoxanthin was significant after adjustments were made for total energy and protein intakes and for cigarette smoking.

Conclusion: These data are consistent with previous evidence showing that a modest increase in ß-cryptoxanthin intake, equivalent to one glass of freshly squeezed orange juice per day, is associated with a reduced risk of developing inflammatory disorders such as rheumatoid arthritis.

Key Words: Prospective study • dietary ß-cryptoxanthin • antioxidant • inflammatory polyarthritis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The role of oxidative damage to the synovium in the pathogenesis of rheumatoid arthritis (RA) and other inflammatory disorders has been recognized for a long time. Circulating antioxidants have a role as scavengers of free radicals and may inhibit oxidative damage and lead to the suppression of inflammation (1, 2). It was recently postulated that this phenomenon might have a role in the prevention of cardiovascular disease. Specifically, reports from epidemiologic studies have shown that C-reactive protein and oxidized LDL-cholesterol concentrations, which have also been linked to the development of cardiovascular disease, are inversely related to serum concentrations of circulating antioxidants, including the carotenoids ß-carotene, ß-cryptoxanthin, and zeaxanthin (3–6). Although cross-sectional studies of serum antioxidant concentrations in patients with RA are consistent with inflammation that results in a relative depletion of antioxidants (7), the data are also consistent with the hypothesis that antioxidants may be protective against the development of RA. Two nested case-control studies, using serum samples collected before the onset of RA, suggested that serum concentrations of antioxidants are reduced before RA onset (8, 9). It is not known whether dietary carotenoid intake is also negatively related to RA onset.

The Iowa Women's Health Study, a large, prospective population-based study of >29000 women aged 55–69 y who completed a food-frequency questionnaire at baseline (1986) and were followed up by questionnaires to determine the onset of various diseases, recently reported a protective effect against the development of RA of a high dietary intake of ß-cryptoxanthin but not of other carotenoids, including ß-carotene, lutein, and zeaxanthin (10). Methodologic reasons may explain the lack of association with the other carotenoids, such as random misclassification of dietary intake, incomplete data on the carotenoid content of some foods, or lack of statistical power. Alternatively, the mechanisms of action of the carotenoids may vary, whereby the influence of ß-cryptoxanthin on some markers of inflammatory activity may be greater than those of other carotenoids (4).

Robust epidemiologic studies of risk factors for RA require the ascertainment of incident cases. One problem that we have identified in such studies is that subjects with a recent onset of inflammatory polyarthritis (IP) are likely to eventually develop RA over a period of several years (11). Therefore, ideally, such studies should aim to recruit all eligible subjects with IP (12) and undertake subsequent subgroup analyses, where appropriate, of those subjects that ultimately satisfy the criteria for RA.

We recently showed that a low dietary intake of vitamin C is a risk factor for the development of IP (13). In that study we also found that high intakes of fruit, but not of vegetables, protect against IP, which would be consistent with a differential role for ß-cryptoxanthin. We have also shown that obesity is associated with an increased risk of developing IP and RA (14), which is of particular interest because a recent report found that in the general population obesity is negatively related to serum concentrations of ß-cryptoxanthin and positively related to C-reactive protein (15). Thus, we investigated the hypothesis that high dietary intakes of some carotenoids, specifically ß-cryptoxanthin, zeaxanthin, lutein, ß-carotene, and lycopene, are protective against the development of IP.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study design
A nested, case-control study embedded within a population-based prospective study was undertaken. The participants in the prospective study had completed a 7-d diet diary at baseline. The baseline dietary intakes of carotenoids and other nutrients were compared between cases (new cases of IP arising within the study population between 1993 and 2001) and their matched controls.

Baseline survey
The subjects studied were recruited as part of the Norfolk arm of the European Prospective Investigation of Cancer Incidence study (EPIC-Norfolk). Details of the EPIC-Norfolk study have been published elsewhere (16). In brief, >25000 subjects aged 45-74 y were identified from registers of primary care physicians and invited to participate in a major prospective study. At baseline, the subjects had their height (in m) and weight (in kg) measured with the use of standard techniques, and they completed a health and lifestyle questionnaire, which included details about current and past smoking habits.

Dietary assessment
The subjects were required to complete a 7-d diet diary in which they recorded all food and beverages consumed over 7 consecutive days. The subjects were encouraged to record the quantities consumed as accurately as possible by using household measures and a series of food portion photographs. This survey method was extensively validated within the EPIC-Norfolk study population, and repeated dietary assessments were shown to reflect dietary intake over a 1-y period. Pearson correlation coefficients between 2 repeat diaries over 1 y were as follows: energy, 0.71; protein, 0.67; vitamin C, 0.59; and ß-carotene, 0.47 (17–20).

Ascertainment of inflammatory polyarthritis
Coincidentally, the population screened within EPIC-Norfolk was under continuous surveillance for the onset of all new cases of IP as part of the Norfolk Arthritis Register (NOAR). Details of NOAR have also been published elsewhere (21). In brief, all new adult attendees to primary care physicians, within the area served by the former Norwich Health Authority, with an onset of joint inflammation affecting ≥2 joints and persisting for >4 wk were alerted to NOAR. On notification, the affected subjects were interviewed and examined by a skilled research nurse and had blood samples taken and analyzed for the presence of rheumatoid factor. The American College of Rheumatology (ACR) classification criteria for RA (22) were applied at baseline and annually thereafter (11). Although there are 7 ACR criteria, it may take time from symptom onset to reach ≥4 criteria, which is the currently accepted cutoff applied in RA comparative studies.

Study participants
The database of subjects participating within EPIC-Norfolk was linked to the NOAR database, and those subjects who had participated in EPIC-Norfolk and who went on to develop IP after the baseline assessments were identified. The subjects were excluded if the inflammation affecting ≥2 joint groups could not be confirmed by the research nurses or if a diagnosis other than RA, psoriatic arthritis, viral arthritis, or undifferentiated polyarthritis was made either at baseline or at follow-up assessments. The remaining subjects were then selected as cases for the current analysis. For each case, 2 control subjects were selected from the EPIC-Norfolk database and were matched for age (to within 3 y), sex, and to within 3 mo of the recruitment to EPIC-Norfolk. All participants had consented to participation, and both the EPIC-Norfolk and the NOAR studies had been approved by the local medical research ethics committee.

Analysis
The dietary data were interpreted by one of us (DJP) and then analyzed for nutrient intake by using the Data Into Nutrients for Epidemiologic Research (DINER) software package, which is based on standard UK food-composition tables (23). Daily intakes of ß-cryptoxanthin, zeaxanthin, lutein, lycopene, ß-carotene, and vitamin C and total energy intake were estimated with the use of a recently extended and updated database of the carotenoid content of foods. For the analyses, nutrient intakes were stratified into tertiles of intake, and total energy intake was entered into the statistical models as a continuous variable. The referent group for each analysis was the group that was presumed the most at risk of developing IP; that is, those in the lowest tertile of intake for each of the carotenoids analyzed. A conditional logistic-regression analysis was undertaken to maintain the matched trios. The risk of developing IP in the 2 higher tertiles of intake for each of the carotenoids was investigated first by univariate analysis and then by multivariate analysis after adjustments for total energy intake, total protein intake [which was previously found to be associated with the risk of developing IP (13)], intake of each of the carotenoids that were not being investigated, vitamin C intake, and pack-years of smoking. Within individuals, carotenoid intakes were not highly correlated; hence, all carotenoid intakes were included in the multivariate analysis. All analyses were performed with STATA 8.0 (24).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
In total, 88 cases that satisfied the entry criteria for this analysis were identified and successfully matched with 176 controls. The mean (±SD) interval between the EPIC-Norfolk survey and the onset of IP was 2.5 ± 1.8 y, and 35 of 78 cases (45%) with complete data satisfied the criteria for a diagnosis of RA at symptom onset. The baseline characteristics of these 88 cases and their matched controls are shown in Table 1Go. Obviously, the cases and controls were well matched for age and sex but, at the time of their baseline EPIC-Norfolk assessment, the cases were more likely to be current smokers than were the controls. There was no significant difference in body mass index, estimated as wt/ht2, between the 2 groups.


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  		TABLE 1 Characteristics of the cases and controls

 
Median dietary intakes of total energy (in kcal), protein (as a percentage of total energy intake), and carotenoids for cases and controls are shown in Table 2Go. There were no significant differences in the intakes of ß-carotene, lutein, and lycopene between the 2 groups. The median zeaxanthin intake was 20% lower and the median ß-cryptoxanthin intake was almost 40% lower in cases than in controls and both differences were statistically significant.


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  		TABLE 2 Daily intake of total energy and antioxidants by cases and controls1

 
ß-Cryptoxanthin and zeaxanthin intakes in the highest tertiles of intake were associated with a reduced risk of developing IP (Table 3Go). Thus, cases were less likely to be in the highest third of intake of ß-cryptoxanthin than were controls [odds ratio (OR): 0.51; 95% CI: 0.25, 1.02], but the association was not statistically significant. After adjustments were made for total energy intake, protein intake, and cigarette smoking, the association was significant (OR: 0.42; 95% CI: 0.20, 0.88). There was a strong correlation between the intakes of ß-cryptoxanthin and vitamin C (r = 0.8); thus, we anticipated that adjusting for vitamin C intake would attenuate any association observed, and indeed this was the case. After adjustment for vitamin C intake, ß-cryptoxanthin intake was no longer significantly correlated with the risk of developing IP, although the estimation changed only slightly (OR: 0.50; 95% CI: 0.22, 1.20). The analysis for zeaxanthin intake showed that cases were also significantly less likely to be in the highest tertile of intake (OR: 0.48; 95% CI: 0.24, 0.94), but after adjustments for the above covariates, the 95% CI included unity (OR 0.52; 95% CI: 0.26, 1.02). There was no association between ß-carotene, lutein, or lycopene intakes and the risk of developing IP (Table 3Go). Thus, although there is a correlation between vitamin C intake and ß-cryptoxanthin intake, adjustment for the former produced an effect estimate for ß-cryptoxanthin that was little altered, although the CI widened.


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  		TABLE 3 Associations between antioxidant nutrient intakes and risk of developing inflammatory polyarthritis1

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In summary, we found that diets high in ß-cryptoxanthin, and probably zeaxanthin, are associated with a reduced risk of developing IP. The extent of these associations, on the whole, persisted after adjustments for vitamin C intake, although the 95% CIs then included unity. Hence, these data are supportive, but not conclusive, of the fact that these carotenoids are independently associated with a reduced risk of IP. Interestingly, these data are also consistent with our previous observation that high-fruit diets may be protective against developing IP (13) and with one other study of diet and RA onset, which used a less intensive method of diet inquiry than the present study, and found that ß-cryptoxanthin intake may have a stronger association with the onset of joint inflammation than do other dietary carotenoids (10).

The present study had several strengths. The study was population-based with regard to both the baseline survey (16) and the identification of subsequent cases of IP (21), which provides external validity to the findings. The cases were identified on the basis of detailed and standardized subject assessment (21). The study was prospective and, hence, free of both subject bias and recall error with relation to the dietary assessment. Additionally, the 7-d diet diary method may be considered, in general terms, to be the most robust method for dietary assessment (19, 25), although serum ß-carotene, ß-cryptoxanthin, and zeaxanthin concentrations also showed moderate correlations with dietary carotenoid intakes when measured by a food-frequency questionnaire (26).

Despite the large sample surveyed in the EPIC-Norfolk study, the number of incident cases of IP was modest, which likely limited both the power to detect a true dose-response relationship and the ability to identify independent associations with specific carotenoids in the present study. The diet diary method of assessment may also be less useful than other dietary assessment methods when the nutrients under investigation occur in food items that are consumed infrequently. In previous studies, we showed that the diet diary was repeatable when assessed through comparisons of one diary with another at different seasons over 1 y and with comparisons of biomarkers of dietary intake, urinary nitrogen, potassium, sodium, and plasma ascorbic acid (18). However, we were unable to assess the repeatability of the dietary intake of ß-cryptoxanthin, which is present in significant quantities in only a few commonly eaten fruit (particularly oranges, bell peppers, and some tropical fruit). Hence, any relation between ß-cryptoxanthin and IP shown in the present study is likely to be attenuated. Additionally, because the control subjects were matched for time of recruitment with the case subjects, seasonal variations would not have accounted for these findings. The intake of ß-cryptoxanthin in this report is higher than those reported by others (10, 27). This is most likely explained by the recent update of the database that lists the carotenoid content of foods, which now gives a more comprehensive estimate of the consumption of ß-cryptoxanthin from foods that are commonly consumed in the United Kingdom. In our subjects, ß-cryptoxanthin intake was attributed mainly to the consumption of oranges, orange juice, and satsumas.

The outcome of interest in this study was the risk of developing IP and not RA specifically. First, our hypothesis was that some antioxidant nutrients protect against inflammation and, thus, we wanted to ensure that all cases of inflammatory arthritis were included. Second, the classification of individuals with a new onset of IP as having RA can be difficult (12). Briefly, the criteria for the diagnosis of RA were developed from observations of individuals with long-standing RA and thus are not easily applied at the time of disease onset. We have shown within NOAR that the cumulative rate of satisfying criteria for RA in individuals with IP continues to increase with time (11). A subgroup analysis showed no obvious differences between those who did and those who did not satisfy the diagnostic criteria by the time of our analysis.

A few reports agree with the suggestion that RA itself may result in reduced concentrations of serum antioxidants. Two small case-control studies found that RA was associated with a reduction in vitamin A (7) and other antioxidants (28). In the latter study, supplementation with ß-carotene did not reduce inflammatory activity (28), although an uncontrolled study suggested that changing to a diet high in antioxidant nutrients might lead to an improvement in RA symptoms (29). However, the present study, which is based on the prospective assessment of the dietary intake of carotenoids, is more supportive of a causal relation between diets that are low in such antioxidants and RA, rather than reduced concentrations of antioxidants being a consequence of RA.

In the present study, the strongest relation was observed between ß-cryptoxanthin intake and IP onset, which supports the finding from the Iowa Women's Health Study of an inverse association between high ß-cryptoxanthin intakes and RA onset (10). Our finding also supports evidence from the Framingham Heart Study, which showed a stronger correlation between dietary intake and serum concentrations of ß-cryptoxanthin than other carotenoids (26). Finally, some data suggests that a high BMI is linked to both low levels of ß-cryptoxanthin and high levels of C-reactive protein in the general population (15), which is consistent with the findings in the present study and with our previous work that found that obesity was associated with a greater risk of developing IP(14).

In conclusion, these data add to a growing body of evidence that some dietary antioxidants, such as the carotenoids ß-cryptoxanthin and zeaxanthin as well as vitamin C, may be protective against the development of IP. On the basis of the results of our study, supplementation of diets with just one glass of orange juice per day is sufficient to raise the intake of ß-cryptoxanthin to the highest and most protective tertile of intake. Given the inherent difficulty of a randomized trial and the rarity of the disease, it may be difficult to prove the contribution of diet to the primary prevention of RA. However, there is perhaps sufficient evidence to suggest a trial to test whether an increase in the consumption of foods that are high in dietary carotenoids and other antioxidant nutrients during early inflammatory joint disease decreases the risk of persistent disease and possibly joint damage.


   ACKNOWLEDGMENTS
 
We acknowledge the collaboration of the rheumatologists in Norfolk led by David Scott and the major contribution by the NOAR and EPIC-Norfolk research nurses. We also acknowledge the work done by Subodha Shakya Shrestha, EPIC-Norfolk, who updated the carotenoid content of foods database.

AJS, DPMS, SAB, and NED were primarily responsible for the study design and contributed to the preparation of the manuscript. AW participated in the design of the study and assisted with the data acquisition and interpretation. DJP assisted with the data acquisition and was responsible for the statistical analysis and the preparation of the manuscript. ML advised on statistical analysis and assisted in interpreting the data. None of the authors had any conflicts of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication November 2, 2004. Accepted for publication March 23, 2005.





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