Introduction

Emerging evidence suggests that poor oral health may play a role in gastrointestinal carcinogenesis through inflammatory and microbiome-mediated mechanisms. However, its association with esophageal cancer remains insufficiently explored.

Aims & Methods

We aimed to assess the association of oral health indicators and oral hygiene behaviors with esophageal cancer risk using both dental health screening and claims-based data. We conducted a population-based case-control study using the Korean National Health Insurance Service (NHIS) database and the National Health Screening (NHS) records. To enhance the reliability of our study, we examined oral hygiene from two complementary perspectives: (1) oral health assessed through dental examinations and questionnaires in the NHS database and (2) periodontal disease status determined based on a claim-based analysis of the NHIS database. Individuals newly diagnosed with esophageal cancer were identified and matched at a 1:4 ratio to cancer-free controls through rigorous propensity score (PS) matching based on sociodemographic factors, comorbidities, lifestyle behaviors, and laboratory parameters. Oral health variables were assessed using national dental screening program data (status of decayed, missing, and filled teeth; gingivitis severity; dental calculus; and self-reported oral hygiene practices) and NHIS claims data identifying periodontal disease using ICD-10 codes and procedure codes. Multivariable-adjusted conditional logistic regression analyses were performed to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CIs).

Results

After PS matching, the oral health analysis included 4,238 cancer cases and 16,904 controls, while the claim-based periodontal disease analysis comprised 18,905 cancer cases and 75,604 matched controls in the final analysis. In multivariable analysis, missing teeth (adjusted OR, 1.16; 95% CI, 1.08–1.25) and inadequate oral hygiene behaviors—including brushing fewer than three times daily (aOR, 1.14; 95% CI, 1.07–1.23), infrequent toothbrushing before bedtime (aOR, 1.08; 95% CI, 1.00–1.16), infrequent use interdental cleaning tools (aOR, 1.10; 95% CI, 1.01–1.19), and dental visits in the past year (aOR, 1.09; 95% CI, 1.02–1.16)—were significantly associated with an increased risk of esophageal cancer. Additionally, claim-based periodontal disease was independently associated with elevated risk (aOR, 1.05; 95% CI, 1.01–1.09). Subgroup analyses revealed consistent associations across smoking and obesity strata, while sex-, age-, and alcohol-stratified analyses demonstrated differential patterns.

Conclusion

This study provides comprehensive, population-based evidence that both clinically assessed dental health indicators and behavioral oral hygiene practices are associated with esophageal cancer risk. The integration of screening-based and claims-based data enhances the validity of the findings and highlights oral health as a potential modifiable risk factor for esophageal cancer prevention.

Introduction

Currently, the only management option for patients with celiac disease (CeD) is lifelong adherence to a gluten-free diet (GFD). Here, we report the results of a phase 2 study of the computationally designed glutenase TAK-062 (zamaglutenase) for the treatment of CeD in patients on a GFD (NCT05353985).

Aims & Methods

Eligible patients were aged >18 years with ongoing CeD-related gastrointestinal (GI) symptoms and villous height to crypt depth ratio (Vh:Cd) <2.5, despite maintenance of a GFD for ≥1 year. Study phases were: (1) a 4-week screening period to confirm symptoms and perform endoscopy; (2) a 4-week single-blind placebo run-in, including 2 weeks receiving placebo simulated inadvertent gluten exposure (SIGE) bars (Weeks −4 to −2) and 2 weeks receiving SIGE bars containing approximately 500 mg of gluten 3× per week (TIW; Week −2 to Day 1); and (3) a 24-week treatment period with patients randomized to receive TAK-062 600 mg or placebo with meals 3× per day (TID), plus gluten-containing SIGE TIW, followed by an endoscopy. Symptoms were assessed daily using the 5-item Celiac Disease Symptom Diary v2.1 (CDSD), that evaluates the severity of CeD symptoms on a 5-point Likert scale.

The primary endpoint was change from baseline to Week 12 in mean weekly CDSD GI symptom severity scores, and the secondary endpoint was change from baseline to Week 24 in Vh:Cd. Safety was assessed throughout the study. Differences between groups were assessed using a mixed model for repeated measures (primary endpoint) and ANCOVA (secondary endpoint) at a 2-sided significance level of 0.05.

Results

A total of 153 patients were randomized (placebo: n = 76; TAK-062: n = 77); one patient in the TAK-062 arm did not receive treatment. Mean age was 46.0 years, 75.2% of patients were female, mean time since diagnosis was 8.7 years, and 24.2% were seropositive. Mean baseline Vh:Cd was 1.78 and mean baseline weekly CDSD GI symptom severity score was 0.93. There were no appreciable differences between groups in baseline characteristics.

There was no significant improvement in weekly CDSD GI symptom severity score from baseline to Week 12 in either arm, and no significant difference between groups; non-significant improvements of approximately 0.1 were observed in both arms (Table). Vh:Cd remained stable to Week 24 in the placebo arm, but significantly decreased by 0.34 (95% confidence interval: −0.53, −0.14) in the TAK-062 arm, with a significant difference between groups (Table). Similar results were observed in all subgroups assessed.

TAK-062 was clinically well tolerated despite the significant decrease in Vh:Cd, with comparable proportions of patients in both arms experiencing an adverse event (AE) (placebo: 64.5%; TAK-062: 73.7%) or serious AE (placebo: 5.3%; TAK-062: 1.3%). The most frequent AEs were GI-related and occurred at a similar frequency in both arms, with the exception of diarrhea (placebo: 2.6%; TAK-062: 17.1%).

Conclusion

TAK-062 did not demonstrate efficacy for improving symptoms or histology in patients with ongoing active CeD on a GFD. Vh:Cd significantly worsened in the TAK-062 arm, with a significant difference between groups; possible reasons for this are under investigation. Stable Vh:Cd in the placebo arm indicates that SIGE successfully mitigates trial-related disease improvements previously observed in similar cohorts.

Disclosure

LE has nothing to disclose. ML reports receiving consulting fees from Anokion, EllaOla, and Takeda, and research funding from Moderna (institution) and Takeda (institution). PR has nothing to disclose. CC has nothing to disclose. JS reports receiving consulting fees from Chugai, GIG, and Takeda, and research funding from Takeda. JAM reports grants from ImmusanT, National Institutes of Health, Department of Defense, Immunogenix, Takeda Pharmaceuticals, Allakos, Provention Bio, Oberkotter Foundation, and 9 Meters Biopharma; a contract (to institution) from Kanyos Bio (a wholly owned subsidiary of Anokion); consultancy fees from Johnson and Johnson, Bristol Myers Squibb, Intrexon Corporation, Dren Bio, Neoleukin Therapeutics, Reistone Biopharma, Immunic Therapeutics, Senda Biosciences, Brightseed Bio, Chugai Pharma, Alimentiv, Equillium, Interlude Biopharma, Ukko Inc., argenx; has received royalties from Torax Medical and Evelo Biosciences; and holds shares in Entero Healthcare and Minnesota Medical Technologies. DSS reports receiving honoraria and research funding from Takeda. HL, JRM, MZ, SG, and DAL are employees and shareholders of Takeda.