Being Overweight or Obese and Risk of RA Among Women
Being Overweight or Obese and Risk of RA Among Women
Our study included a total of 109 896 women in NHS and 108 727 women in NHSII contributing 2 765 195 person-years of follow-up from 1976 to 2008 (32 years) in NHS and 1 934 518 person-years of follow-up from 1989 to 2009 (20 years) in NHSII. We validated 1181 incident cases of RA (826 in NHS, 355 in NHSII). Table 1 summarises the baseline characteristics of NHS and NHSII participants by BMI category. The prevalence of obesity was 8.3% in NHS and 11.8% in NHSII. NHS women, on average, were older at enrolment (mean age 42.9 (SD±7.2) years) compared with NHSII women (mean age 34.4 (SD±4.7) years). NHS RA cases were, on average, about 10 years older than NHSII RA cases at diagnosis of RA (age 57.9 vs age 47.6) with 41% of RA cases and 83% of NHSII RA cases diagnosed at or before 55 years of age. A higher proportion of NHSII participants reported never smoking, higher levels of physical activity, and oral contraceptive use.
The age-adjusted incidence rate of RA was 30/100 000 person-years in NHS, ranging from 27 to 32/100 000 person-years, and 18/100 000 person-years in NHSII, ranging from 12 to 27/100 000 person-years, across increasing categories of BMI. These incidence rates are lower than that previously reported in Rochester, Minnesota, USA, yet consistent with prior reports from Massachusetts, USA, and other European countries. In analyses of time-varying BMI, we observed a trend toward increased risk of RA among overweight and obese women (pooled HR (95% CI) were 1.37 (0.95 to 1.98) and 1.37 (0.91 to 2.09), p for trend=0.068)) compared to women of normal BMI, that was statistically significant in NHSII, but not in NHS (Table 2). In analyses restricted to those women diagnosed with RA at age 55 years or younger (312 cases in NHS, 306 cases in NHSII), the association appeared stronger in both cohorts with the pooled HR of 1.45 (1.03 to 2.03) for overweight women and HR 1.65 (1.34 to 2.05) for obese women. The PAR % for overweight and obesity was 10% in NHS and 40% in NHSII. When we repeated our analyses stratifying cases by RA serologic status, we observed comparable positive associations between overweight and obesity and seropositive and seronegative RA, and associations were also stronger for RA cases diagnosed at earlier ages (Table 2). By contrast, when we restricted to RA cases whose diagnosis age was over 55 years, we did not observe a significant association between BMI and risk of RA (data not shown), though this was limited by small numbers of older onset RA cases in NHSII. There was no statistically significant difference in the association between BMI and RA among heavy smokers (≥10 pack years) compared to light or non-smokers (<10 pack years) (p for interaction was 0.550 in NHS, 0.486 in NHSII, see online supplementary table S1 http://ard.bmj.com/content/73/11/1914/suppl/DC1). Similarly, no significant interactions were observed between BMI and age or physical activity on risk of RA in both cohorts.
Analyses using cumulative average BMI demonstrated that being overweight or obese was significantly associated with increased risk of RA overall (pooled HR 1.23 (1.06 to 1.44) for obese women, 1.34 (1.06 to 1.68) for overweight women) (Table 3). For RA cases diagnosed at age 55 years or younger, the pooled HR was 1.26 (1.01, 1.57) for overweight women and HR 1.51 (1.20 to 1.88) for obese women. Additionally, using an alternative way to measure the long-term effect of obesity, the number of years of obesity was also associated with risk of RA only among those diagnosed at age 55 years or younger. Ten cumulative years of being obese, conferred a 37% increased risk of RA onset ≤ age 55 years (HR 1.37, 95% CI 1.11 to 1.69). When stratified by serologic status, this 10-year obesity risk was significant among seropositive RA cases (HR 1.37 (1.10 to 1.71) but not among seronegative cases. The results from lagged analyses, using BMI measures at 4 years and 6 years prior to RA diagnosis, were consistent with those of time-varying BMI and cumulative average BMI demonstrating a reduced likelihood for observed associations to be due to reverse causation. Also, we observed that being in the upper range of normal BMI (23.0–24.9 kg/m) and overweight at age 18 years was only associated with increased risk of seropositive RA, but not seronegative RA in pooled analysis (Table 4). The sensitivity analysis with additional adjustment for women's reproductive factors (menarche age, parity/breastfeeding, menopausal status and postmenopausal hormone use), demonstrated no major change in point estimates or significance of the findings. The lagged analyses and analyses excluding cancer cases gave similar results. And lastly, in NHSII, sensitivity analyses replacing pregnancy weights with non-pregnant weights from the prior cycle, demonstrated no difference from the primary results.
Results
Our study included a total of 109 896 women in NHS and 108 727 women in NHSII contributing 2 765 195 person-years of follow-up from 1976 to 2008 (32 years) in NHS and 1 934 518 person-years of follow-up from 1989 to 2009 (20 years) in NHSII. We validated 1181 incident cases of RA (826 in NHS, 355 in NHSII). Table 1 summarises the baseline characteristics of NHS and NHSII participants by BMI category. The prevalence of obesity was 8.3% in NHS and 11.8% in NHSII. NHS women, on average, were older at enrolment (mean age 42.9 (SD±7.2) years) compared with NHSII women (mean age 34.4 (SD±4.7) years). NHS RA cases were, on average, about 10 years older than NHSII RA cases at diagnosis of RA (age 57.9 vs age 47.6) with 41% of RA cases and 83% of NHSII RA cases diagnosed at or before 55 years of age. A higher proportion of NHSII participants reported never smoking, higher levels of physical activity, and oral contraceptive use.
The age-adjusted incidence rate of RA was 30/100 000 person-years in NHS, ranging from 27 to 32/100 000 person-years, and 18/100 000 person-years in NHSII, ranging from 12 to 27/100 000 person-years, across increasing categories of BMI. These incidence rates are lower than that previously reported in Rochester, Minnesota, USA, yet consistent with prior reports from Massachusetts, USA, and other European countries. In analyses of time-varying BMI, we observed a trend toward increased risk of RA among overweight and obese women (pooled HR (95% CI) were 1.37 (0.95 to 1.98) and 1.37 (0.91 to 2.09), p for trend=0.068)) compared to women of normal BMI, that was statistically significant in NHSII, but not in NHS (Table 2). In analyses restricted to those women diagnosed with RA at age 55 years or younger (312 cases in NHS, 306 cases in NHSII), the association appeared stronger in both cohorts with the pooled HR of 1.45 (1.03 to 2.03) for overweight women and HR 1.65 (1.34 to 2.05) for obese women. The PAR % for overweight and obesity was 10% in NHS and 40% in NHSII. When we repeated our analyses stratifying cases by RA serologic status, we observed comparable positive associations between overweight and obesity and seropositive and seronegative RA, and associations were also stronger for RA cases diagnosed at earlier ages (Table 2). By contrast, when we restricted to RA cases whose diagnosis age was over 55 years, we did not observe a significant association between BMI and risk of RA (data not shown), though this was limited by small numbers of older onset RA cases in NHSII. There was no statistically significant difference in the association between BMI and RA among heavy smokers (≥10 pack years) compared to light or non-smokers (<10 pack years) (p for interaction was 0.550 in NHS, 0.486 in NHSII, see online supplementary table S1 http://ard.bmj.com/content/73/11/1914/suppl/DC1). Similarly, no significant interactions were observed between BMI and age or physical activity on risk of RA in both cohorts.
Analyses using cumulative average BMI demonstrated that being overweight or obese was significantly associated with increased risk of RA overall (pooled HR 1.23 (1.06 to 1.44) for obese women, 1.34 (1.06 to 1.68) for overweight women) (Table 3). For RA cases diagnosed at age 55 years or younger, the pooled HR was 1.26 (1.01, 1.57) for overweight women and HR 1.51 (1.20 to 1.88) for obese women. Additionally, using an alternative way to measure the long-term effect of obesity, the number of years of obesity was also associated with risk of RA only among those diagnosed at age 55 years or younger. Ten cumulative years of being obese, conferred a 37% increased risk of RA onset ≤ age 55 years (HR 1.37, 95% CI 1.11 to 1.69). When stratified by serologic status, this 10-year obesity risk was significant among seropositive RA cases (HR 1.37 (1.10 to 1.71) but not among seronegative cases. The results from lagged analyses, using BMI measures at 4 years and 6 years prior to RA diagnosis, were consistent with those of time-varying BMI and cumulative average BMI demonstrating a reduced likelihood for observed associations to be due to reverse causation. Also, we observed that being in the upper range of normal BMI (23.0–24.9 kg/m) and overweight at age 18 years was only associated with increased risk of seropositive RA, but not seronegative RA in pooled analysis (Table 4). The sensitivity analysis with additional adjustment for women's reproductive factors (menarche age, parity/breastfeeding, menopausal status and postmenopausal hormone use), demonstrated no major change in point estimates or significance of the findings. The lagged analyses and analyses excluding cancer cases gave similar results. And lastly, in NHSII, sensitivity analyses replacing pregnancy weights with non-pregnant weights from the prior cycle, demonstrated no difference from the primary results.
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