This study reports the most recent trends in RA incidence in a population-based US cohort. We demonstrated a modest increase in RA incidence among women during the period from 1995 to 2007. This increase followed a sharp decline in RA incidence observed over the previous 4 decades. As expected, the increased incidence was accompanied with an increase in the prevalence of RA.
From the middle of the 20th century, RA occurrence has been widely studied in multiple centers, predominantly in the US and Western Europe (1
). Despite the variable disease frequency reported for different populations, all these studies (including our own) showed a compelling decline in RA incidence over the period 1955-1994. Very few epidemiological studies have reported secular trends in RA incidence after 1995. Pedersen et al. demonstrated an increasing incidence of RA in from 1995-2001, particularly in women(23
). These findings are consistent with our own. Kaipiainen-Seppänen et al. compared RA incidence in 1980, 1985, 1990, 1995 and 2000, verifying the previously observed declining trend in our cohort(5
). The observed declines in that study were less apparent among cases >64 years of age where a modest increase in incidence was shown from 1980 to 2000(10
). This increasing trend in RA incidence is concordant with our data. However, unlike these other reports, we did not observe a difference in increase of RA incidence among different age-groups.
Below we speculate on the possible explanations for the modest increase in RA incidence observed in our study. Oral contraceptives (OC) have been clearly shown to be associated with a dose dependent protective effect against the development of RA in women(1
). Modern day OC contain significantly lower doses of synthetic estrogens as compared to OC used decades ago(30
). Because these lower doses of synthetic estrogens confer less protection against the development of RA than higher doses, it is almost certain that the protective effect of OC has diminished over time. Thus, this exposure may contribute to the observed increase in RA incidence in women.
Breastfeeding is another gender-specific factor reported to have a dose-dependent protective effect against the development of RA(32
). Moreover, rates of breastfeeding in the US have been increasing in recent years(34
). However, this protective effect is limited to the population of parous women who chose breastfeeding, and the effects are most significant among those who choose long-time (>24 months) breastfeeding, an even smaller number. Therefore, this factor is unlikely to have a major impact on RA incidence.
Cigarette smoking is perhaps the strongest environmental risk factor clearly associated with the development of RA in both genders(35
). While smoking is less prevalent in the US in general, smoking rates are declining at a significantly slower pace among women compared to men. Thus, the gap in the proportion of male and female smokers has significantly and progressively narrowed since 1965(43
). The slower decline in smoking rate among women can, in part, explain the lack of decline in RA incidence rate among women.
Several lines of evidence suggest that vitamin D deficiency may be associated with the development of RA(44
). In addition, vitamin D deficiency has been demonstrated to be increasing over the previous decades, particularly in women(44
). Thus, vitamin D deficiency may also contribute to the observed RA incidence trends.
A number of other environmental factors postulated to play a role in RA incidence, especially in women, may also be implicated in the observed trends. These include infections, immunizations, obesity, socioeconomic status, etc.(51
While speculative, the above findings, when taken together, suggest that the cumulative effect of multiple environmental factors (each associated with either an increased in risk or a loss in protection, particularly in women) could explain the observed rise in RA incidence over the study period. Besides those mentioned, the effect of other, unknown risk factors on the changes in RA incidence over time cannot be excluded.
Our study has several important strengths including its longitudinal population-based design and the use of a systematic and standardized approach to case identification. Study limitations include the possibility of an increased awareness of RA in recent years, potentially including the awareness of the 1987 ACR criteria for RA. The increase in female RA incidence without changes in male incidence and lack of differences in incidence of RF positive and RF negative RA argues against ascertainment bias. Small sample size and resulting lack of statistical power could be responsible for our inability to detect a change in incidence in males. While it is possible that the observed increase in incidence in RA females merely represents a lack of decline, we believe this is unlikely because the increase was observed across a number of years. Furthermore, there is a possibility of underascertainment of cases in studies involving medical record review. However, the comprehensive and standardized approach to case ascertainment described in methods makes selection bias unlikely. Finally, the population of Olmsted County, MN is 90% white suggesting that the results of our study may not be generalizable to other, more racially diverse populations. Furthermore, the demographic characteristics in Olmsted County, MN (including survival rates, aging, race, % of emigrants) have not changed substantially over the recent years and were thus unlikely to influence the observed epidemiological trends.
In conclusion, we observed that the incidence of RA appears to be rising during the period from 1995 to 2007. This rise in incidence followed a period of 4 decades of declining incidence and appeared to be limited to women. The reasons for this increase in incidence are unknown, but environmental factors likely play a role.