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Previous studies linking periodontal disease with increased risk for rheumatoid arthritis (RA) -- and the reverse as well -- failed to account for a critical confounding factor that explains nearly all of the apparent correlation, a new study from Denmark suggests.

Results from an analysis covering some 2.6 million Danes, followed from 2000 to 2017, indicated that "periodontitis may slightly, but practically negligibly, increase the risk of incident RA, whereas RA did not increase the risk of incident periodontitis," according to Eero Raittio, DDS, PhD, of Aarhus University in Denmark, and colleagues.

Moreover, they , "after adjusting for age, sex, country of birth, and dental service use, the residual cross-sectional association between these conditions was completely explainable by the confounding of smoking."

Multiple earlier studies had found strong associations between periodontal disease and subsequent development of RA, and some also found that the presumed causal direction could point the other way, too -- RA was seen to promote development of periodontal disease. One of these studies suggested that anti-citrullinated protein antibodies, frequently seen in RA and thought to contribute to its pathology, originate with periodontal disease.

But Raittio and colleagues argued that their findings should prompt "reconsideration of the biologic plausibility and clinical significance of these associations."

These researchers acknowledged that it had made sense to find common ground between the two conditions. Periodontal disease and RA share important features, such as inflammation and destruction of connective tissue and bone, such that one "could potentially trigger or exacerbate the progression of the other."

But Raittio and colleagues found fault with the previous studies, noting that most were meant as case-control studies but weren't designed correctly. "Few, if any, of the studies carrying the case-control moniker [in this field] follow a proper case-control design" that would allow causality to be inferred, Raittio's group argued. Rather, they wrote, those studies' designs were more like "case vs non-case," based on convenience samples in which the controls weren't necessarily drawn from the same population as cases.

"Moreover, the timing of periodontitis detection in RA cases may be unknown or may occur over a considerable time period (e.g., over 10 years) after RA onset, which may hamper establishing the temporal sequence of these conditions," Raittio and colleagues complained. Other studies that the group considered stronger had not found an association between RA and periodontal disease, including that adjusted for many potential confounders including smoking.

For their own study, Raittio's team pulled national registry data for all Danish adult residents from 1990 to 2018 -- a total of about 6.6 million -- which they then whittled down by half to include only those still alive and a resident in Denmark, younger than 80, and free of both RA and periodontal disease in 2000. This sample was also analyzed in 2017 after excluding some 734,000 who had died or left the country by then, for a total of 2.6 million. The "bidirectional association" between periodontal disease and RA -- that is, impacts of RA on development of periodontal disease along with the reverse -- were estimated over this 18-year follow-up period, via survival analysis in which individuals' records were examined year by year to determine whether either disease had been diagnosed.

Median age in this population was 43 in 2000 and 57 in 2017. About two-thirds had used dental services in these years; the median number of years in which people saw dentists during follow-up was 7.

The survival curves showed very little difference in rates at which RA was diagnosed in people with periodontitis versus those without, whether or not adjustments were taken for sociodemographic parameters and presence of type 2 diabetes. While adjusted analyses did show a statistically significant increase in RA risk with periodontitis (HR 1.05, 95% CI 1.01-1.09), Raittio's team called it "negligibly small," and noting that the difference in survival time amounted to "approximately 1 calendar day over an 18-year follow-up."

Oddly, the probability of remaining periodontitis-free were slightly greater for people with RA. Raittio and colleagues reported that the "estimated effect of RA on incident periodontitis was 0.84 (95% CI 0.80-0.88)" after applying inverse probability weights, which was nearly the same as what they found in unadjusted data (HR 0.85, 95% CI 0.81-0.89). This, too, was not clinically important when analyzed by survival time, the researchers argued: the difference in mean time to develop periodontitis between those with and without RA was 151 days over the 18 years of follow-up.

Importantly, the registry records did not include people's smoking status. However, the researchers simulated it from published survey data and other sources (i.e., 23% of people with RA were considered active smokers as of 2017, versus 17% among those without RA). In this model, the small increase in RA risk with periodontitis vanished entirely (prevalence ratio 0.99, 95% simulation interval 0.93-1.04). Smoking is a well-recognized risk factor for both RA and periodontal disease.

Limitations to the study included some uncertainty in diagnosis of periodontitis, which was not recorded explicitly in the national registries but was inferred from procedure codes. Also, the smoking simulation only modeled yes-or-no current smoking, without taking account of intensity or past smoking history.

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