Gout is an excruciatingly painful inflammatory arthritis caused by the crystallization of uric acid within joints. Based on the National Health and Nutrition Examination Survey 2007–2008, the prevalence of gout in the US is estimated to be 3.9% among US adults, which translates into 8.3 million US adults (1, 2). While the pathophysiology of gout is well-characterized and efficacious pharmacologic regimens are available, many patients with gout continue to experience recurrent gout attacks (3, 4). Such attacks cause tremendous pain and are a major cause of morbidity.
Over the past few decades, cherries have garnered considerable public attention and interest from both patients and investigators as a potentially effective option in the prevention and management of gout. Small experimental studies in healthy human subjects and animals have demonstrated that cherry consumption lowers serum uric acid levels (5, 6). Others have shown that cherry products contain high levels of anthocyanins (7–9), which possess antiinflammatory and antioxidant properties (8, 10–12). Furthermore, some cherry producers have claimed that cherry products have the potential to reduce the pain associated with gout (13), and some patients use cherries as a strategy to avoid and/or treat gout attacks (14). However, to our knowledge, no study has assessed whether consumption of cherries lowers the risk of gout attacks, as reflected in warning letters sent to various cherry-based product manufacturers by the Food and Drug Administration about the lack of sufficient data regarding their claims of disease-related benefits of cherry products (13).
To help address this relevant knowledge gap, we analyzed 633 gout patients who were prospectively recruited from across the US in an online gout study (15). In this study, we used a case–crossover design to quantify the relative risk of gout attack after cherry intake as compared with no cherry intake and its potential modification by allopurinol use and major gout risk factors.
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- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
A total of 633 patients with gout completed both hazard-period and control-period questionnaires over a consecutive 12-month period between February 2003 and February 2010. Of them, 554 (87.5%) met the ACR preliminary criteria for the classification of gout. The characteristics of the participants are presented in Table 1. The average age of the participants was 54 years. Participants were predominantly men (78%), white (88%), and over half had received a college education. Subjects were recruited from 49 states and Washington, DC. Approximately 61% of the participants consumed alcohol, 29% used diuretics, 45% took allopurinol, 54% used NSAIDs, and 25% took colchicine during either the hazard or control periods.
Table 1. Characteristics of the 633 participants in the internet-based case–crossover study of gout*
|Sex, male||494 (78.0)|
|Age, median (range)||54 (21–88)|
|BMI, median (range), kg/m2||30.6 (14.7–69.9)|
| African American||19 (3.0)|
| White||558 (88.2)|
| Other||47 (7.4)|
| Refused to answer||9 (1.4)|
| Less than high school graduate||10 (1.6)|
| High school graduate||55 (8.7)|
| Some college/technical school||199 (31.4)|
| College graduate||157 (24.8)|
| Some professional/graduate school||70 (11.1)|
| Completed professional or graduate school||142 (22.4)|
|Annual household income, $|| |
| <25,000||51 (8.1)|
| 25,000–49,999||127 (20.1)|
| 50,000–74,999||121 (19.1)|
| 75,000–99,999||89 (14.1)|
| ≥100,000||163 (25.8)|
| Refused to answer||82 (13.0)|
|Disease duration, median (range) years||5 (1–49)|
|Alcohol use||383 (60.5)|
| Diuretics||184 (29.1)|
| Allopurinol||285 (45.0)|
| NSAIDs||342 (54.0)|
| Colchicine||160 (25.3)|
During the 1-year followup period, we documented 1,247 gout attacks. Most gout attacks occurred in the lower extremity (92%), particularly in the first metatarsophalangeal joint, and had features of either maximal pain within 24 hours or redness (89%). Approximately 90% of gout attacks were treated with colchicine, NSAIDs, systemic corticosteroids, intraarticular corticosteroid injections, or a combination of these medications. The median time between the onset of gout attack and completion of the hazard-period questions was 3 days.
Of the 633 participants included in the analysis, 224 (35%) reported ingesting fresh cherry fruit only, 15 (2%) cherry extract only, and 33 (5%) both fresh cherry fruit and cherry extract during hazard periods, control periods, or both. As shown in Table 2, cherry intake over a 2-day period was associated with a 35% lower risk of gout attacks compared with no intake (multivariate OR 0.65 [95% CI 0.50–0.85]). The risk of gout attacks tended to decrease with increasing cherry consumption up to 3 servings over 2 days; however, further intake did not appear to provide a greater protective effect. Cherry extract intake was associated with a 45% lower risk of gout attacks (multivariate OR 0.55 [95% CI 0.30–0.98]). When we additionally adjusted for caffeinated beverage intake and number of servings of vegetables consumed over the past 2 days, the results did not change materially (OR 0.65 [95% CI 0.50–0.85]).
Table 2. Cherry or cherry extract intake in prior 2 days and risk of gout attacks*
|Variable||Number of control periods||Number of hazard periods||Crude OR (95% CI)||Adjusted OR (95% CI)†|
|Cherries only|| || || || |
| No||1,318||1,074||1.0 (referent)||1.0 (referent)|
| Yes (any amount)‡||271||173||0.69 (0.54–0.89)||0.65 (0.50–0.85)|
| 1 serving||71||53||0.92 (0.62–1.36)||0.98 (0.65–1.48)|
| 2 servings||98||56||0.59 (0.40–0.89)||0.52 (0.34–0.79)|
| 3 servings||35||16||0.48 (0.25–0.92)||0.39 (0.20–0.77)|
| ≥4 servings||67||48||0.69 (0.44–1.09)||0.62 (0.38–1.00)|
|Cherry extract only|| || || || |
| No||1,520||1,212||1.0 (referent)||1.0 (referent)|
| Yes||69||35||0.59 (0.34–1.04)||0.55 (0.30–0.98)|
|Cherries or cherry extract|| || || || |
| No||1,278||1,052||1.0 (referent)||1.0 (referent)|
| Yes||311||195||0.68 (0.53–0.86)||0.63 (0.49–0.82)|
When we limited the analysis to participants who met the ACR preliminary criteria for the classification of gout (n = 554), the multivariable OR of recurrent gout attacks was 0.65 (95% CI 0.50–0.85) for cherry intake over a 2-day period. In addition, when we varied the definition of recurrent gout attacks by requiring specific features individually or in combination, the results did not change materially. For example, when we limited the analysis to those that had ≥2 of the 4 features (antigout medication use, podagra, maximal pain within 24 hours, and redness) (n = 606), the multivariable OR was 0.63 (95% CI 0.48–0.82).
The inverse association with cherry intake persisted across subgroups divided by sex and body mass index. Multivariate ORs for cherry intake and the risk of recurrent gout attacks were 0.68 (95% CI 0.51–0.91) among men and 0.48 (95% CI 0.27–0.83) among women (P for interaction = 0.28). The corresponding ORs were 0.57 (95% CI 0.40–0.80) among obese individuals and 0.72 (95% CI 0.49–1.04) among nonobese individuals (P for interaction = 0.35).
Table 3 summarizes the combined effects of cherry intake and various gout-related risk factors or medications on the risk of gout attacks. Increase in alcohol consumption and purine intake as well as use of diuretics were associated with a higher risk of recurrent gout attacks, whereas use of allopurinol and use of colchicine were associated with a lower risk of gout attacks. There was no association between NSAID use and risk of recurrent gout attacks (Table 3). The effect of cherry intake on the risk of recurrent gout attacks tended to be stronger when cherries or cherry extract were consumed during periods of higher purine intake or alcohol abstention, and when diuretics or NSAIDs were not used. Notably, when cherry intake was combined with allopurinol use, the risk of gout attacks was 75% lower than without either exposure (OR 0.25 [95% CI 0.15–0.42]). None of these factors showed significant interaction with the effect of cherry intake (P for interaction > 0.17).
Table 3. Cherries or cherry extract intake in prior 2 days and risk of gout attacks in subgroups of patients divided by purine intake, alcohol consumption, use of diuretics, and use of antigout drugs*
|Risk factors over 2 days||Cherry or cherry extract intake over 2 days†||Number of control periods||Number of hazard periods||Adjusted OR (95% CI)‡|
|Purine intake|| || || || |
| >1.7 gm (high)||No||536||604||1.00 (referent)|
| >1.7 gm (high)||Yes||152||119||0.60 (0.44–0.83)|
| ≤1.7 gm (low)||No||742||448||0.46 (0.37–0.57)|
| ≤1.7 gm (low)||Yes||159||76||0.32 (0.22–0.47)|
|Alcohol use|| || || || |
| Yes||No||622||495||1.00 (referent)|
| Yes||Yes||140||98||0.92 (0.70–1.20)|
| No||No||656||557||0.77 (0.53–1.10)|
| No||Yes||171||97||0.50 (0.34–0.74)|
|Diuretic use|| || || || |
| Yes||No||238||270||1.00 (referent)|
| Yes||Yes||65||58||0.74 (0.46–1.20)|
| No||No||1,040||782||0.37 (0.24–0.58)|
| No||Yes||246||137||0.22 (0.13–0.36)|
|Allopurinol use|| || || || |
| No||No||870||792||1.00 (referent)|
| No||Yes||205||150||0.68 (0.50–0.92)|
| Yes||No||408||260||0.47 (0.34–0.63)|
| Yes||Yes||106||45||0.25 (0.15–0.42)|
|Colchicine use|| || || || |
| No||No||1,097||930||1.00 (referent)|
| No||Yes||269||173||0.66 (0.46–0.97)|
| Yes||No||181||122||0.61 (0.47–0.80)|
| Yes||Yes||42||22||0.52 (0.27–0.98)|
|NSAID use|| || || || |
| No||No||954||770||1.00 (referent)|
| No||Yes||223||135||0.59 (0.44–0.79)|
| Yes||No||324||282||1.00 (0.78–1.30)|
| Yes||Yes||88||60||0.77 (0.49–1.19)|
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
In this large study of prospectively recruited patients with preexisting gout, we found that cherry intake was associated with a 35% lower risk of recurrent gout attacks, and intake of cherry extracts showed a similar inverse association. These associations were independent of other risk factors, including factors that did not vary with time, such as genetics, sex, race, and education (by study design) and that varied with time, such as purine intake, alcohol consumption, and the use of antigout medications and diuretics. Interestingly, when cherry intake was combined with the use of allopurinol, the most commonly used urate-lowering drug, the risk of gout attacks was 75% lower than during the period without either exposure.
Several biologic mechanisms have been elaborated to link cherry consumption to the risk of gout attacks. A study conducted among 10 healthy women showed that consumption of cherries, but not other fruits, such as strawberries, grapes, or kiwi fruit, significantly reduced levels of both serum uric acid and plasma creatinine (5). These findings led investigators to speculate that cherries may exert their urate-lowering effect through increasing the glomerular filtration rate or reducing tubular reabsorption. In an animal study, intake of tart cherry juice significantly decreased the levels of serum uric acid in rats with hyperuricemia by inhibiting the hepatic activity of xanthine oxidase and xanthine dehydrogenase, suggesting that cherries may possess the capacity to reduce uric acid production (6). Cherries and cherry extract contain high levels of anthocyanins (7–9) that exert antiinflammatory effects either through inhibiting cyclooxygenase activity (8, 10–12) or via scavenging of nitric oxide radicals (23). Thus, cherries may also have antiinflammatory properties against the series of inflammatory responses triggered by monosodium urate crystals. Although cherries contain vitamin C, the amount they include (∼80 mg in 6 servings of cherries) (5) is likely to be too low to have an impact on the risk of gout, since the relevant vitamin C dosages associated with a reduction in serum uric acid levels and gout risk have been shown to be ∼500 mg/day or higher (24–26).
Our findings suggest that these data on the potential influence of cherries on levels of serum uric acid (5) and potential antiinflammatory effects (8, 10–12) may be translated into prevention of gout attacks among patients with preexisting gout. While urate-lowering therapy (e.g., allopurinol in >90% of cases in the US and Europe) can be efficacious in lowering levels of serum urate and the risk of gout when dosed appropriately and used compliantly, current practice standards limit urate-lowering therapy to specific indications, such as frequent gout attacks, tophaceous gout, and advanced gout, primarily due to rare but serious side effects (27). When these indications are not yet met, nonpharmacologic options, such as risk factor modifications, are the only acceptable preventive approach. Should our findings be confirmed in randomized clinical trials, cherries or cherry extracts could provide a novel nonpharmacologic option for preventing gout attacks. Furthermore, our findings regarding the combined use of cherries and allopurinol also suggest that cherries may add substantially to the effects of allopurinol in preventing gout attacks in gout patients.
Identifying potential triggers for recurrent gout attacks is challenging when using traditional study designs and recruiting methods. To address these issues, we adapted a case–crossover study design to examine a set of potential triggers, including cherry intake, in relation to the risk of recurrent gout attacks. This study design is highly adaptable to evaluating the effect of transient exposure as a trigger for acute disease onset, and self-matching of each subject minimizes bias in control selection and removes the confounding effects of the factors that are constant over the study period but differ between participants (e.g., genetic factors, sex, race, education) (28). We also used the internet as a platform to conduct the study. As our study and others have demonstrated, the internet is an efficient way to access a large number of potential participants and to collect information in real time (29, 30), thereby minimizing recall bias.
The present study has some limitations. While the case–crossover study design is optimal for assessing the acute effects of cherry intake, it is not ideal for evaluating the long-term effects of habitual cherry consumption. Because cherry consumption was self-reported by questionnaire, some misclassification of exposure is possible despite our use of pictures to depict different serving sizes during our data collection. If gout attacks somehow triggered more recollection of cherry intake, it would have biased the potential protective effects of cherry intake toward null. Furthermore, our cherry effect estimates were independent of other well-established antigout measures, such as allopurinol, colchicine, and NSAIDs. Nevertheless, our study was observational; thus, we cannot rule out the possibility that unmeasured factors might have contributed to the observed associations.
We did not collect data on serum uric acid levels; thus, we were unable to assess whether cherry consumption decreased the risk of gout attacks even among subjects whose serum uric acid levels were below the therapeutic target levels (e.g., 6 mg/dl). However, when we limited our analysis to subjects who reported taking allopurinol on online questionnaires (n = 184), the risk of recurrent gout attacks was still decreased with cherry consumption, even though allopurinol use itself was associated with a lower risk of recurrent gout attacks. In our study, the antigout benefits of cherry consumption peaked at ∼3 servings over a 2-day period and tended to attenuate at the next higher consumption level, although remaining protective. While certain opposing mechanisms, such as fructose included in sweet cherries, might play a role at certain levels of cherry consumption, as has been shown for oranges and apples (31, 32), we cannot rule out random variations due to relatively small sample sizes in the highest consumption categories. Thus, these findings need be confirmed in future studies. Finally, we were unable to estimate the absolute rates of gout attacks using the case–crossover study design, and the distribution of cherry intake among the participants in our study may not be representative of a random sample of US patients with gout; however, the biologic effects of cherry intake on gout attacks (as reflected in our OR estimates) should be similar.
In conclusion, our findings suggest that cherry intake is associated with a lower risk of gout attacks. Should our findings be confirmed in randomized clinical trials, cherry products could provide a novel nonpharmacologic option for the prevention of gout attacks.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Zhang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Zhang, Neogi, Chaisson, Hunter, Choi.
Acquisition of data. Zhang, Neogi, Chen, Chaisson, Hunter, Choi.
Analysis and interpretation of data. Zhang, Neogi, Chaisson, Hunter, Choi.