To the best of our knowledge, this is the first study to conduct a bidirectional two-sample MR analysis to comprehensively estimate the causal relationship between PD and different serotypes of RA. Our results demonstrated that there was a genetic effect of seropositive RA on PD, which is supported by the findings of previous observational study[18]. Similarly, Pablo et al. found that, after adjusting for age, gender, race, and smoking, RA patients had a significantly increased risk of PD[37]. With respect to MR analysis on RA and PD, there are only limited data available[38, 39] and these studies have yielded inconsistent results. Yin et al. demonstrated that no causal association was found between PD and RA in their MR analysis[39]. Another MR study reported an association between the prevalence of PD and an increased risk of RA, despite having only 7 eligible IVs based on their summary statistics[38]. However, these two studies have a limitation that they treat different serotypes of RA as a whole, whereas different serotypes of RA may have distinct effects on the occurrence of PD[40].
Rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA) are specific autoantibodies associated with RA. Both of these autoantibodies are included in the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA[41]. Seropositive RA is diagnosed when either RF, ACPA, or both are present. Approximately 60–80% of RA patients fall into the seropositive subtype, while 30% of RA patients do not have these autoantibodies and are referred to as having seronegative RA[42]. Although the link between RA and PD has been mostly discussed in terms of ACPA, reports on the different prevalence and manifestations of PD between the two RA serotypes remain inconclusive. It was found that the incidence of PD was as high as 73.3% in ACPA-negative RA patients. Interestingly, according to the 2018 international classification for PD, there were significant differences in the staging of PD between ACPA-positive and ACPA-negative RA patients[18]. Another cross-sectional study identified higher rates of stage I and stage II PD in ACPA-negative RA patients[43]. In present study, no casual association was found between seronegative RA and PD. The inconsistency of the results could potentially be attributed to the small sample size of seronegative RA patients and ethnic variations among different studies.
It has been postulated that the link between RA and PD exists in the ACPA molecules[44]. Certain periodontal pathogens, namely Porphyromonas gingivalis or Aggregatibacter actinomycetemcomitans, may play a significant role in the development of RA owing to their possession of virulence determinants, namely peptidylarginine deiminase and leukotoxin, respectively. These determinants have the potential to contribute to the generation of citrullinated proteins, which in turn may trigger the development of RA-associated autoantibodies[10, 45].
To explore the causal relationship between PD and RA, Mankia et al. conducted a periodontal examination on the seropositive at-risk individuals for developing RA. They identified a significantly higher prevalence of PD in the at-risk population compared with the healthy controls[46]. Similarly, Bello-Gualtero et al.[47] assessed the periodontal condition of individuals with genetic susceptibility to RA and found significantly elevated levels of plaque index, probing bleeding, and severity of PD in this cohort compared with the control group. These research findings suggest that PD may serve as one of the predisposing factors for the development of RA, occurring prior to the onset of RA. However, the results of reverse MR analysis in the present study indicated no causal effect of PD on RA in the studied population. It is important to note that, when interpreting our findings, our study sample consisted of individuals with established RA which differed from the pre-clinical RA population examined in the previous studies. Furthermore, the present study did not include information regarding the treatment history of the participants. These factors may contribute to the contrasting results in the causal connections between PD and RA. Further research incorporating larger sample sizes and considering treatment variables is warranted to better understand the causal relationship between PD and RA.
Based on our findings that there was a causal effect of seropositive RA on PD, it may be advisable for clinicians to recommend seropositive RA patients undergo periodontal examination or treatment to prevent the initiation and development of PD. Considering the chronic inflammatory process in both diseases, it is reasonable to hypothesize that RA treatment, based on host-modulating therapies, could have potential benefits in managing PD development of RA patients. In a study conducted by Pers et al., it was observed that treatment with antitumor necrosis factor-alpha led to an improvement in the clinical attachment loss of RA patients[48]. On the other hand, nonsurgical periodontal treatment appears to have an impact on the RA disease activity[49], although controversial results exist[50]. Future randomized controlled trials with longer follow-up periods will be necessary to gain a better understanding of the impact of periodontal therapy on the progression of RA.