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- SUBJECTS AND METHODS
Through 11 years (314,181 person-years) of followup, 152 cases of RA were validated. Demographic and clinical characteristics are presented in Table 1. The mean age of RA patients at the baseline survey was 61.1 years with a mean age at RA onset of 67.8 years. A majority (>78%) of the cohort was married at baseline, and the mean body mass index was 26.8 kg/m2. The mean time to diagnosis from RA symptom onset was ∼1 year (mean 13.4 months). Factors that may be indicative of poor health practices (education, employment status at baseline, place of residence at baseline, occupation at baseline, physical activity at baseline) did not show any differences between cases and noncases across levels of total vitamin D intake and were not associated with RA risk in this cohort.
Table 1. Demographics at the Baseline Survey and Clinical Characteristics of Subjects with or without Rheumatoid Arthritis (RA), Iowa Women's Health Study, 1986–1997*
|With RA (n = 152)||Without RA (n = 29,368)|
|Age, mean ± SD years||61.1 ± 3.9||61.5 ± 4.2||0.23|
|Body mass index, mean ± SD kg/m2||26.8 ± 4.6||26.8 ± 4.9||0.84|
|Vitamin D intake, IU/day, median (IQR)|| || || |
| Food and supplements||272.5 (338.7)||336.0 (377.9)||0.06|
| Food only||206.6 (193.6)||221.1 (193.8)||0.34|
| Supplements only||0 (200)||0 (400)||0.10|
|Marital status, %|| || || |
| Currently married||84.9||78.7||0.07|
| Never married||2.6||2.5|
|Hormone replacement therapy, %|| || || |
| Never used||55.3||61.0||0.11|
| Formerly used||34.9||27.3|
| Currently use||9.9||11.6|
|Smoking status, %|| || || |
| Never smoked||58.4||66.7||0.005|
| Former smoker||20.1||19.6|
| Current smoker||21.8||13.7|
|Decaffeinated coffee, cups/day, %|| || || |
| None||36.8||42.7|| |
| ≥2.6||34.9||25.7|| |
|Age at RA onset, mean ± SD years||67.8 ± 4.9||–|| |
|Average time from RA onset to diagnosis, mean ± SD months||13.4 ± 21.7||–|| |
|ACR RA criteria (16) satisfied, mean ± SD||4.6 ± 1.1||–|| |
There was a strong correlation between vitamin D intake from food only and calcium intake from food only (r = 0.84). The strongest correlation between vitamin D and calcium intake derived from individual food items was that with skim milk. The correlation between total vitamin D intake and total calcium intake was moderate (r = 0.54). The association between vitamin D intake from food and risk of RA did not vary by the level of calcium consumption from food, nor did the association between total vitamin D intake and risk of RA vary by level of total calcium consumption. Therefore, no effect modification was seen.
The associations of RA with vitamin D intake from both diet and supplement use are presented in Table 2. Greater intake (highest versus lowest tertile) of total daily vitamin D was inversely associated with risk of RA (RR 0.67, 95% CI 0.44–1.00, P for trend = 0.05). Inverse associations were apparent for both dietary (RR 0.72, 95% CI 0.46–1.14, P for trend = 0.16) and supplemental (RR 0.66, 95% CI 0.43–1.00, P for trend = 0.03) vitamin D. These measures of effect remained robust after adjustment for multiple confounders.
Table 2. Relative Risks (RRs) and 95% Confidence Intervals (95% CIs) for Risk of Rheumatoid Arthritis According to Intake of Vitamin D from Food and Supplements, Iowa Women's Health Study, 1986–1997
|Vitamin D measure, IU/day*||Cases||Person-years||Age-adjusted RR (95% CI)||Multivariable-adjusted RR (95% CI)†|
|Total|| || || || |
| <221.4||64||103,613||1.00 (referent)||1.00 (referent)|
| 221.4–467.6||42||103,741||0.64 (0.43–0.97)||0.67 (0.45–1.01)|
| ≥467.7||46||106,827||0.67 (0.45–1.00)||0.67 (0.44–1.00)|
| P for trend|| || ||0.05||0.05|
|Dietary|| || || || |
| <169||59||103,586||1.00 (referent)||1.00 (referent)|
| 169–289.9||50||103,750||0.81 (0.55–1.21)||0.87 (0.58–1.29)|
| ≥290||43||106,845||0.68 (0.44–1.06)||0.72 (0.46–1.14)|
| P for trend|| || ||0.09||0.16|
|Supplemental|| || || || |
| Nonusers||109||200,008||1.00 (referent)||1.00 (referent)|
| <400||13||37,423||0.64 (0.36–1.14)||0.65 (0.36–1.15)|
| ≥400||30||76,750||0.69 (0.46–1.04)||0.66 (0.43–1.00)|
| P for trend|| || ||0.05||0.03|
Total calcium intake from all sources was not associated with risk of RA (data not shown). However, calcium from dietary sources was suggestive of an inverse trend (RR 0.69, 95% CI 0.44–1.10, P for trend = 0.11) for the highest tertile of dietary calcium intake relative to the lowest. However, this association disappeared (P = 0.50) when total vitamin D intake was included in the model. No RA association was seen with supplemental calcium use.
Relationships of individual food items containing vitamin D and/or calcium with the risk of RA are presented in Table 3. No individual food item high in vitamin D content and/or calcium was strongly associated with RA risk. A composite score of servings of milk products combined was inversely associated with risk of RA (RR 0.66, 95% CI 0.42–1.01, P for trend = 0.06). This association persisted even when supplemental vitamin D intake was included in the model.
Table 3. RRs and 95% CIs for Risk of Rheumatoid Arthritis According to Intake of Vitamin D and Calcium-Containing Dairy Products, Iowa Women's Health Study, 1986–1997*
|Dairy product, servings/month||Cases||Person-years||Age-adjusted RR (95% CI)||Multivariable-adjusted RR (95% CI)†|
|Milk products‡|| || || || |
| 1–35||58||98,352||1.00 (referent)||1.00 (referent)|
| 36–67||52||107,109||0.80 (0.54–1.17)||0.80 (0.54–1.18)|
| ≥68||42||108,720||0.63 (0.41–0.98)||0.66 (0.42–1.01)|
| P for trend|| || ||0.04||0.06|
|Butter|| || || || |
| None||115||217,020||1.00 (referent)||1.00 (referent)|
| ≥1||37||97,161||0.70 (0.48–1.02)||0.72 (0.49–1.06)|
|Margarine|| || || || |
| None||23||36,462||1.00 (referent)||1.00 (referent)|
| 1–21||24||66,612||0.58 (0.33–1.04)||0.56 (0.31–1.02)|
| 22–74||46||104,300||0.73 (0.44–1.22)||0.71 (0.43–1.19)|
| ≥75||59||106,807||0.96 (0.58–1.58)||0.92 (0.56–1.52)|
| P for trend|| || ||0.49||0.58|
|Skim milk|| || || |
| None||40||73,802||1.00 (referent)||1.00 (referent)|
| 1–3||11||16,334||1.23 (0.63–2.40)||1.23 (0.63–2.40)|
| 4–29||34||74,235||0.84 (0.53–1.33)||0.85 (0.53–1.36)|
| ≥30||67||149,810||0.82 (0.55–1.21)||0.87 (0.58–1.30)|
| P for trend|| || ||0.24||0.39|
|Whole milk|| || || || |
| None||122||253,034||1.00 (referent)||1.00 (referent)|
| ≥1||30||61,147||1.04 (0.70–1.56)||1.04 (0.69–1.57)|
There was a suggestion of interaction between vitamin D and smoking (P = 0.17) (data not shown). For smokers with high vitamin D intake, there was a trend toward an inverse association with RA (RR 0.66, 95% CI 0.32–1.22), whereas smokers with low vitamin D intake were at increased risk for RA (RR 1.8, 95% CI 1.16–2.75) (both comparisons relative to nonsmokers with low vitamin D intake).
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- SUBJECTS AND METHODS
In this prospective cohort study of older women, we found an inverse association between greater intake of vitamin D and RA risk. The association persisted even after potentially confounding variables were included in the analyses. Vitamin D from supplements showed a stronger inverse association with RA development than did dietary vitamin D. No individual food item high in calcium or vitamin D was associated with RA. Lower serum levels of vitamin D and dietary intake of vitamin D in smokers have been reported by investigators in several studies (11). Since smoking may deplete vitamin D, we evaluated this possibility and found a suggestive interaction between smoking and vitamin D, although this was an exploratory analysis.
Vitamin D has immunologic activity independent of its crucial role in calcium regulation (12). Animal models of autoimmune disease have shown beneficial effects of vitamin D as an immunosuppressant. For example, murine models of human RA demonstrated both decreased incidence and severity of disease in mice treated with active vitamin D (3). Evidence supporting an effect of vitamin D in RA specifically also is derived from clinical observations. Manolagas et al found that a significantly greater proportion of seropositive RA patients (76%) had lymphocytes possessing vitamin D receptors compared with controls (18%) (13). Within the rheumatoid joint, the active form of vitamin D has been shown to be synthesized in RA synovium and is thought to be stimulated by interleukin-1 (IL-1) and/or IL-2 (14). Locally produced vitamin D may act in a paracrine manner to decrease T cell responsiveness through the inhibition of cellular proliferation and reduction in lymphokine production when confronted by an inappropriate and overly exuberant immune response (15).
Since high calcium levels exert negative feedback on the synthesis and action of vitamin D, we examined effects of calcium as well. In our study, the high correlation between calcium and vitamin D from food and the only moderate correlation of total calcium intake with total vitamin D intake, which included supplemental vitamin D, may have been due to vitamin D fortification of calcium-containing foods. Our results did not show an effect modification by calcium and vitamin D intake on the incidence of RA. Calcium from food sources, which was strongly correlated with vitamin D from food sources, appeared to be inversely associated with RA. However, this association was no longer significant when vitamin D was included in the model, suggesting a greater effect of vitamin D.
The strengths of this study include its population-based prospective design and rigorous case validation. This study utilized a validated food frequency questionnaire, although consumption was assessed only at baseline. In many dietary studies, low vitamin levels may be the result of dietary changes due to the disease and/or treatment effects themselves. However, in this cohort, dietary assessment occurred before disease onset.
In addition to its strengths, there are limitations to this study. Subjects were not clinically examined and some may have been misclassified, which is less of a concern in this study due to the large comparison group. Additionally, older adults, such as the women in the IWHS, tend to have low levels of vitamin D intake, which may have influenced our results. However, this effect would presumably be nondifferential between RA and non-RA cases and, if anything, would create a bias toward the null hypothesis. A potentially important source of vitamin D is from sun exposure, which was not measured in this study. Since sunlight exposure substantially affects vitamin D levels, this might represent a source of unmeasured confounding. Although the participation of mainly elderly white women from the state of Iowa should not influence the validity of our findings, it may limit their generalizability. Finally, our findings were not based on an a priori hypothesis; it is therefore possible that chance alone explains these results. However, there is a compelling biologic explanation for these findings.
In summary, greater intake of vitamin D showed an inverse association with incident RA in this cohort of elderly women. While the immunomodulatory effects of vitamin D are not yet fully elucidated, the results from this study suggest a possible role for vitamin D in reducing the risk of an immunologic disorder. These results are largely hypothesis generating; further studies will be required to corroborate or refute our findings.