Resumen de Tumor Necrosis Factor-? and Oral Inflammation in Patients With Crohn Disease
Background: Crohn disease (CD) is a chronic inflammatory bowel disease often accompanied by periodontal symptoms. Based on its function in immune response, tumor necrosis factor (TNF)-? and its genetic variants have been discussed as risk indicators in inflammatory processes. Therefore, the aim of the present study is to investigate the impact of TNF-? polymorphisms on periodontal parameters and inflammatory lesions of oral mucosa as a characteristic of CD.
Methods: A total of 142 patients with CD were included in the study. Oral soft tissue alterations and periodontal parameters were assessed. Genotypes, alleles, and haplotypes of TNF-? polymorphisms (rs1800629, cDNA-308G > A; and rs361525, cDNA-238G > A) were determined by polymerase chain reaction with sequence-specific primers (PCR-SSP).
Results: Patients with CD who exhibit more severe oral soft tissue alterations were significantly more often A allele carriers of rs361525 than G allele carriers (14.2% versus 2.2%; P <0.001). Furthermore, A allele carriers had a higher mean periodontal probing depth (P <0.05), mean clinical attachment level (P <0.05), and sites with bleeding on probing (not significant). Similar results were obtained when evaluating A allele-containing genotypes (AG + AA) and haplotypes (GA). In multivariate analyses considering age, sex, smoking, and medication as confounders, the A allele was proven to be an independent risk indicator for oral soft tissue alterations in patients with CD. No genotype-dependent influence of rs1800629 was observed.
Conclusion: The TNF-? A allele of rs361525 represents a significant risk indicator for oral soft tissue alterations in patients with CD.
Crohn disease (CD) is characterized as a chronic inflammatory disease primarily involving the intestinal tract. Oral manifestations have been described as special characteristics of CD and are supposed to precede intestinal manifestation.1,2 The most affected oral areas are the buccal mucosa, gingiva, lips, and vestibular and retromolar regions.
A multitude of risk factors affect the development of CD, including bacterial infections, inflammatory mediators, and genetic predisposition. It was demonstrated that oral infections are manifest in patients with CD and could influence the clinical outcome of CD.3 The inflammation of the periodontium could result in the initiation and progression of systemic inflammatory response, possibly leading to the medical condition of CD. Moreover, periodontal lesions and intestinal symptoms were shown to coincide.4 Consistent with these hypotheses, it was demonstrated that patients with CD reveal a higher prevalence, severity, and extent of periodontitis in the Jordanian population,3 but others confirmed in patients with CD only a moderate severity of periodontal disease and a higher occurrence of the periodontal pathogen Campylobacter rectus.5,6 Concordances in the etiology of CD and periodontitis might be based on the existence of common exogenous and endogenous risk factors. Aberrations in the sensitively controlled cytokine network are supposed to represent an initial step in the etiopathology of periodontitis and CD potentially linking both diseases.7,8 Among the inflammatory candidate genes, tumor necrosis factor (TNF)-? has been in the focus of intensive research for a long time.9,10 TNF-? as a potent proinflammatory cytokine is released at the site of inflammation. Elevated levels of this cytokine could be detected in the gastrointestinal tract and stool of patients with CD, as well as in the crevicular fluid of patients with periodontitis.11 Furthermore, it has been shown that the level of TNF-? is elevated in the saliva of patients with CD.12 This elevation was in agreement with the prevalence of oral lesions, including gingivitis, cobblestoning, buccal swelling, or ulcer in patients with CD.
Anti-TNF-? therapy was reported to have a striking beneficial clinical effect in most patients with CD.13 Data concerning the advantage for patients with periodontitis receiving anti-TNF-? therapy are inconsistent.14 Although anti-TNF-? agents can reduce oral production of inflammatory cytokines, their effect on periodontal inflammation is controversial. In patients suffering from rheumatic arthritis, the administration of anti-TNF-? medication resulted in an increase in the gingival index (GI) and bleeding on probing (BOP) in one study,15 whereas others showed decreased GI and BOP.16 However, these data cannot be generalized because all of the patients suffered from rheumatic arthritis and the study size was limited (n = 9 versus n = 9;15 n = 10 versus n = 1016). Furthermore, it was shown that the success of anti-TNF-? therapy is dependent on, among other factors, the genetic characteristics of the TNF-? gene.17 A multitude of single nucleotide polymorphisms (SNPs) have hitherto been described in the TNF-? gene.18 SNPs in the TNF-? promoter cDNA�308G > A (rs1800629) and cDNA-238G > A (rs361525) belong to the most extensively studied genetic variants in this gene. In clinical and in vitro studies, the importance of these SNPs on its expression was highlighted.19,20 Because of its functional relevance, these SNPs were evaluated as risk markers for a variety of inflammatory diseases. Possible associations of genetic variants in the TNF-? gene with CD and periodontitis were comprehensively investigated in clinical studies, including genome-wide association studies.21,22 However, the impact of the TNF-? SNPs rs1800629 and rs361525 on the susceptibility to both inflammatory diseases is controversially discussed.
In the present case-control study, the impact of the TNF-? SNPs rs1800629 and rs361525, including their genotypes, alleles, and haplotypes, on periodontal parameters and the occurrence of oral soft tissue lesions were investigated in patients with CD in bivariate and complex risk models.
