Response to the Letter to the Editor,“Sjögren’s Disease Is Not a Clinical Risk Factor for Periodontitis”

We appreciate Vissink et al.’s comment on our Mendelian randomization (MR) study. The studies included in the meta-analysis by Maarse et al. (2019) had a cross-sectional or case-control (CS/CC) design and sparse sample sizes. With a CS/CC design, reverse causation cannot be ruled out, and low power may explain why no associations (even between Sjögren’s disease [SjD] and plaque index) were found (Maarse et al. 2019). The available longitudinal studies used claims or registry data and regression or matching to adjust for confounders (Lin et al. 2019; Chuang et al. 2020; Aga et al. 2023). Meta-analysis of observational studies produces biased pooled estimates if the individual studies are subject to residual confounding (Egger et al. 1998). We applied a different analytic strategy with independent bias to examine the same underlying question and strengthen the evidence (Lawlor et al. 2016). MR’s quasi-experimental design is relatively immune to reverse causation and unobserved confounding. Our study found a positive effect of SjD on periodontitis (PD), and sensitivity analysis supported underlying instrumental variable assumptions. The genetic associations were derived from a genome-wide association study with valid phenotyping of PD (Shungin et al. 2019).

Vissink et al. postulate that SjD might induce gingivitis but not PD. In contrast, well-designed longitudinal studies following new SjD cases revealed higher incidences of PD (Chuang et al. 2020). In addition, SjD is unlikely to cause only gingivitis and not PD given that gingivitis is the main modifiable precusory of PD (Chapple et al. 2015). Our MR study triangulates these positive findings. The negative finding of Aga et al. (2023) possibly results from including death as a covariate in their regression model. Adjusting for covariates is an established approach to mitigate confounding but requires comprehensive understanding of causal pathways, as indiscriminate adjustment may increase bias (Etminan et al. 2021).

Author Contributions

S.L. Reckelkamm, contributed to conception, design, data acquisition, drafted and critically revised the manuscript; Z. Alayash, contributed to data interpretation, critically revised the manuscript; B. Holtfreter, contributed to design, data analysis, critically revised the manuscript; M. Nolde, contributed to conception, design, data acquisition, analysis, and interpretation, critically revised the manuscript; S.-E. Baumeister, contributed to conception, design, data acquisition, analysis, and interpretation, drafted and critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work.