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Prevalence of Apical Periodontitis in Patients with Inflammatory Bowel Diseases: A Retrospective Clinical Study
Clinical Research
Prevalence of Apical Periodontitis in Patients with Inflammatory Bowel Diseases: A Retrospective Clinical Study Vanessa Piras, DDS,* Paolo Usai, MD,† Silvia Mezzena, DDS,* Marta Susnik, DDS,* Francesca Ideo, DDS,* Elia Schirru, DDS,‡ and Elisabetta Cotti, DDS, MS* Abstract Aim: We evaluated the prevalence of apical periodontitis (AP) and the oral health status in patients with inflammatory bowel diseases (IBDs) treated with immunomodulators, with particular attention to biologic medications (BMs). Methods: One hundred ten patients, 49 men and 61 women (average age, 46 13.8 years), from the Gastroenterology Unit of the University Hospital with IBDs who were treated with BMs or corticosteroids were included in the study. One hundred ten patients who registered for a dental check-up at the Dental Clinic were matched for age, sex, and physical characteristics with the study group without systemic diseases and not taking medications who were the control. Patients underwent a complete oral, dental, and radiographic examination. Decayed, missing, and filled teeth and periapical index score indexes were recorded. Student t test, c2, and MannWhitney U test were used as appropriate. Results: The prevalence of AP was 64% in IBD patients and 59% in the control; according to the gender-stratified analysis, the difference was not significant among the male groups, whereas the number of teeth with AP was significantly higher in female patients with IBDs than in the controls (P # .05). The prevalence of AP in patients treated with BMs was 65%; women showed 69% higher risk for AP and presented a significantly higher number of teeth with AP (P # .05). Decayed, missing, and filled teeth index was similar in both groups, whereas patients with IBDs had a higher periapical index score than the controls. Conclusions: Women with IBDs and taking immunomodulators had a higher prevalence of AP. All patients with IBDs had larger lesions than healthy subjects. These data emphasize the influence of the status of the immune system in the onset of AP and the need for further studies to confirm these findings. (J Endod 2017;43:389–394)
Key Words Apical periodontitis, biologic medications, inflammatory bowel diseases
I
nflammatory bowel Significance diseases (IBDs) are The development and evolution of apical periodonmultifactorial, idiopathic, titis in patients affected by autoimmune diseases chronic inflammatory disand in treatment with the new immunomodulators orders characterized by need to be considered carefully. diffuse inflammation of the intestinal mucosa. They are associated with dysregulation and inappropriate response of the intestinal mucosal immune system to otherwise innocuous luminal antigens in a genetically susceptible host (1, 2). Crohn’s disease (CD) and ulcerative colitis (UC) are 2 main phenotypes of IBD (3–5). Genetic predisposition (6–9) and deficiencies in the innate immune response can be linked to the development of IBDs. The pathogenesis of IBDs is the result of an imbalance of proinflammatory and antiinflammatory factors (10, 11). UC is characterized by an upregulation of interleukin (IL)-5 and can be considered as a type 2 immune disease, whereas CD exhibits high levels of interferon-g, IL-12, and tumor necrosis factor (TNF) and is classified as a type 1 immune disease prototype (12). First-line treatment (13–15) for IBDs has been centered on immunosuppressive therapy such as disease-modifying anti-inflammatory drugs or corticosteroids (16). Nonsteroidal anti-inflammatory drugs are used to relieve pain and inflammation and treat the symptoms of extraintestinal manifestations of IBDs (arthralgia, arthritis) (17–19). Patients who have not responded to standard therapies are currently being treated with biologic medications (BM), which are predominantly recombinant human proteins with immunoregulatory effects (20–28). Their target is mainly the modulation of proinflammatory cytokines. Anti-TNF agents have been reported to achieve remission of the disease, tapering of glucocorticoids (26, 29), and healing of the mucosa (30). Oral manifestations of IBDs can be found in 4%–16% of patients and include persistent soft tissue swellings, edema of the mucosa, linear ulceration, angular cheilitis, and granulomatous gingivitis (31). Furthermore, IBD patients seem to have increased prevalence of caries and periodontitis (32–38). Apical periodontitis (AP) is a chronic inflammatory disorder of the periradicular tissues caused by an infection of endodontic origin. It is the consequence of a dynamic encounter between root canal microbes and host defenses that results in a local inflam-
From the *Department of Conservative Dentistry and Endodontics, School of Dentistry, and †Department of Gastroenterology, School of Medicine, University of Cagliari, Cagliari, Italy; and ‡Department of Endodontology, Kings College Dental Institute, London, United Kingdom. Address requests for reprints to Dr Elisabetta Cotti, Department of Conservative Dentistry and Endodontics, University of Cagliari Italy, VIA ROMA 149, 09124 Cagliari, Italy. E-mail address: [email protected] 0099-2399/$ - see front matter Copyright ª 2016 American Association of Endodontists. http://dx.doi.org/10.1016/j.joen.2016.11.004
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Clinical Research mation, resorption of hard tissues, and destruction of other periapical tissues driven by complex interactions between immune-inflammatory cells and soluble mediators (39, 40). Prevalence of AP increases with age and varies from 33% to 62% (41). Because no studies to date have investigated the association of IBDs with AP, the purpose of this investigation was to evaluate the prevalence of AP and the oral health status in patients with IBDs, with particular attention to the influence of BMs on AP.
Materials and Methods Medical records of 110 patients affected by IBDs who were referred to the University Dental Clinic for a routine dental evaluation during the period of June 2012–July 2015 were retrospectively studied; data extrapolated were compared with those from 110 healthy patients not subjected to any pharmacologic therapy who visited at the Dental Clinic in the same period. The study was approved by the Institutional Ethics Committee and was in accordance with the Helsinki Declaration of 1975 (as revised in 2000). All participants gave their informed consent before inclusion in the study.
Selection of Cases The patients with gastrointestinal (GI) chronic immune diseases, CD, or UC were recruited for this retrospective study. The eligibility criteria for inclusion were the following: 1. 2. 3. 4.
Male and female patients Age range 18–70 years Affected by a GI chronic immune disease Taking corticosteroids or BM for at least 6 months for the GI disease Exclusion criteria included the following:
1. Patients presenting with other systemic pathologies 2. Patients taking more than 1 medication for the major pathology 3. Patients who did not allow their data to be used A total of 110 records from patients with IBD, 49 men and 61 women (average age, 46 13.8 years), were recruited; 74 patients in treatment with BMs and 36 patients in treatment with corticosteroids who agreed and met the inclusion/exclusion criteria constituted the study group. All these individuals were outpatients attending the Department of Gastroenterology at D. Casula Hospital of the University of Cagliari, Italy. In IBD patients the average period of time in which the disease was present was 12 7.5 years. Diagnosis of CD and UC were performed according to the international investigational protocols (42–46). An additional 110 subjects, 53 men and 57 women (average age, 41 13.1 years), who reported no history of IBD or any clinical sign of ongoing systemic diseases, were matched for age, gender, and socioeconomic status (education, occupation, income), and who also met the inclusion criteria constituted the control group. Patients in the control group were randomly recruited in this retrospective study among the patients from the same health district seeking routine dental examination at the same Dental Clinic for the first time.
Clinical Data Collection and Radiographic Examination All medical records comprised a questionnaire covering demographic data including age, gender, medical history, and medications taken. The medical history records were focused on the collection of relevant information regarding the major IBD disease, the time of onset of the disease, and the previous and current medications taken to treat the disease. A written informed consent for the dental examination, the panoramic radiograph, the addi390
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tional periapical radiographs, and the use of the clinical data were included in all medical records. The medical record review was used to collect the data. The following parameters were assessed: number of teeth in the dental arches, presence of caries, presence of conservative restorations, presence of extensive restorations (conservative/prosthetic), presence of endodontic treatment, presence of apical periodontitis, evaluation of periodontal probing depth, and presence of lesions in the soft tissues (sinus tracts/abscesses/other). The teeth were examined according to the decayed, missing, filled teeth (DMFT) index by using the World Health Organization criteria (47). The evaluation of the panoramic radiographs (used as initial screening) and of all of the selective intraoral radiographs (taken in upper anterior teeth, when scarcely visible, in all teeth that presented restorations, prosthetic restorations, AP, or suspected AP in the panoramic radiograph) available in the medical records were used for the assessment of the periapical status.
Acquisition of Data Medical history, diagnostic, and treatment information for each patient were entered on a collection form and coded for computer entry. At the initial visit, after the evaluation of the panoramic radiograph and the clinical examination, standardized periapical radiographs were taken. Conventional radiographs were obtained by using a film holder for paralleling technique. Exposure times and kilovoltage were adjusted according to the film manufacturer’s instructions. The periapical radiographs were scanned, saved in JPEG format, and transferred to the Image J software (version 1.41; National Institutes of Health, Bethesda, MD) for measurement and recording of the results. The plug-in application TurboReg (Biomedical Imaging Group, Swiss Federal Institute of Technology, Lausanne, VD, Switzerland) was used to mathematically minimize any dimensional changes that might have been incorporated into the preoperative or postoperative radiographs as a result of angulation differences to the x-ray central beam at the time of image acquisition (48). The periapical status was assessed by using the periapical index score (PAI) (49) by 2 trained and calibrated endodontists (weighted kappa values, k = 0.8) (50). For multirooted teeth, the highest of the PAI scores given to the individual roots was used. If the 2 examiners did not agree, the highest of their scores was assigned. The quality of coronal restorations and root canal treatments was assessed by the same 2 examiners on the basis of the criteria described by Ng et al (51). When 1 of the components was not satisfactory, the entire tooth was judged as inadequate. Statistical Analysis The prevalence of AP was evaluated on the total number of individuals and the total number of teeth. Statistical analysis was also differentiated by sex to investigate the possible confounding role of gender on the risk of AP. Descriptive analysis was performed, and the differences between groups were evaluated with Student t test for normal distributed variables, c2, or Mann-Whitney U test as appropriate. A further analysis was performed to assess possible differences between patients treated with BMs and controls; P value # .05 was considered statistically significant. STATA version 13 (STATA Corp, College Station, TX) was used.
Results The prevalence of AP was 64% in the IBD group and 59% in the control (Table 1) (P > .05); the same happened with the number of teeth with AP, which was higher in patients with IBDs compared with the controls (P > .05). Gender-stratified analyses showed a higher JOE — Volume 43, Number 3, March 2017
Clinical Research TABLE 1. Prevalence of AP in IBD and Control Groups and Gender Stratification Overall IBD Control P value Female IBD Control P value Male IBD Control P value
Subjects with AP
Teeth with AP
No. of teeth
DMFT
PAI
64% 59% .489
1 [0–2], 1.63 (2.0) 1 [0–2], 1.16 (1.4) .098*
25 (6.1) 28 (3.5) .0004
9.1 (4.6) 9.2 (5.1) .93
3.9 (1.0) 2.8 (1.1) .0001
59% 51% .374
1 [0–3], 1.83 (2.4) 1 [0–1], 0.98 (1.4) .042*
25 (5.7) 28 (2.9) .0057
10 (4.8) 8.3 (4.3) .046
3.8 (0.97) 8.3 (4.3) .0001
69% 68% .874
1 [0–2], 1.38 (1.2) 1 [0–2], 1.35 (1.4) .58*
25 (6.5) 27 (4.0) .025
8.0 (4.0) 10.1 (5.6) .034
3.9 (1.0) 3.1 (1.1) .0026
Results are presented as percentage frequency, median [I–III quartile], mean (standard deviation). *Wilcoxon rank test.
risk for AP in IBD women compared with the controls (odds ratio [OR], 1.44; 95% confidence interval [CI], 0.86–2.39 and OR, 1.03; 95% CI, 0.61–1.74, respectively; P > .05). All the differences described above were not significant (Table 1). However, women with IBDs had a significantly higher number of teeth with AP (P < .05) (Table 1). Men with IBDs had an equal risk of being affected by AP (OR, 1.07; 95% CI, 0.44–2.48) and no difference in the number of teeth with AP (P > .05) compared with the controls (Table 1). The prevalence of AP among IBD patients taking BMs was not significantly higher than in controls (P > .05), whereas the number of teeth with AP was higher in patients taking BMs (P = .05) (Table 2). Women with IBDs and treated with BMs showed 69% higher risk for AP (OR, 1.69; 95% CI, 0.68–3.9) but not statistically significant (P > .05) (Table 2), yet they exhibited a significantly higher number of teeth with AP (P < .05). Among IBD men there were no differences between the groups in the number of subjects and teeth with AP (P > .05) (Table 2). IBD patients exhibited a significantly higher PAI index when compared with the controls (3.9 vs 2.8; P < .05) and a similar mean DMFT score (9.1 vs. 9.2; P > .05) (Table 1). When divided by gender, IBD women showed a higher DMFT score than controls (P < .05) (Table 1), whereas an opposite trend was evident among men (P < .05) (Table 1). These results were confirmed in BMs subgroup (Table 2). The quality of root canal treatment and coronal restoration of endodontically treated teeth with AP was judged adequate in 63% of teeth in the IBD group and in 68% of teeth in the control group.
Discussion We investigated the prevalence of AP and the oral health status in patients affected by a category of autoimmune diseases (IBDs) and taking immunomodulators, with particular attention to the possible effects of the newly used biologic immune modulators on AP (52). When the patients in the study group received the dental and endodontic evaluation, they had been diagnosed with IBD for an average of 12 7.5 years. We observed that the technical quality of root canal treatment and coronal restorations in the teeth with AP that had been previously treated received a similar score in IBD patients and in controls. On one hand, we found that AP was not significantly prevalent among patients with IBDs; on the other hand, we found that women with IBDs tend to have a higher number of periapical lesions, and when treated with biologics, they are at even higher risk for AP compared with the healthy controls. There is growing evidence that dysbiosis of the gut microbiota contributes to the development of both intestinal and extraintestinal disorders (53). Consequently, IBDs might represent an independent risk factor for the development of chronic oral diseases (54–57), and conversely, the presence of dental diseases may influence the development of IBDs (58, 59). It has already been assessed how the integrity of the nonspecific immune system is one of the key factors in the favorable outcome of endodontic treatment (60) and in the healing time of AP (61), and studies have shown a higher prevalence of AP in diabetic patients (62, 63), with women with long-standing type 1 diabetes exhibiting more root-filled teeth with periapical lesions (64).
TABLE 2. Prevalence of AP in BM and Control Groups and Gender Stratification Overall BM Control P value Female BM Control P value Male BM Control P value
Subjects with AP
Teeth with AP
No. of teeth
DMFT
PAI
65% 59% .43
1 [0–2], 1.66 (1.98) 1 [0–2], 1.16 (1.4) .050*
25 (6.3) 28 (3.5) .0001
9.0 (4.9) 9.2 (5.1) .77
3.8 (1.0) 2.8 (1.1) .0001
63% 51% .26
1 [0–4], 2.0 (2.4) 1 [0–1], 0.98 (1.4) .015*
25 (6.2) 28 (2.9) .0007
10.5 (5.3) 8.3 (4.3) .034
3.9 (0.99) 2.5 (0.87) .0001
67% 68% .89
1 [0–2], 1.35 (1.3) 1 [0–2], 1.35 (1.4) .72*
25 (6.6) 27 (4.0) .033
7.6 (4.2) 10.2 (5.7) .022
3.7 (1.0) 3.1 (1.1) .025
Results are presented as percentage frequency, median [I–III quartile], mean (standard deviation). *Wilcoxon rank test.
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Clinical Research The different behavior of AP, such as the presence of clinical symptoms (65), and the increased susceptibility to persistent AP (66) are also influenced by the genetic polymorphisms associated with the expression of some cytokines. All these consecutive observations keep the focus on the impact that impaired or modulated immune system may have on the onset, evolution, and healing of infections of endodontic origin. Another interesting result comes from the size of AP; the average PAI score was higher in IBD patients treated with immunomodulators than in the controls. This observation would confirm that a chronic systemic autoimmune inflammatory disorder and/or the use of the immunomodulators may influence the periapical status of the compromised teeth. These observations are coherent with results from animal studies that have shown that immune compromised rats and diabetic NOD mice developed a more severe response to pulp infection and larger periradicular lesions (67, 68). However, there is still limited information regarding the effects of IBDs and of the different types of immunomodulators on the development of AP. An unusually fast development of a periapical lesion in a patient affected by rheumatoid arthritis taking azathioprine and corticosteroids was recently reported (69). The reduction of periapical inflammation after the systemic, intramuscular, or local administration of corticosteroids was also described (70–73), whereas opposite results were obtained when a combination of corticosteroids and antibiotic was used as an intracanal medication (74). The data in the literature on BMs and oral infections are mostly limited to periodontitis, which represents a similar model for etiology and pathogenesis to AP. In a primate model of experimental periodontitis, the administration of BMs (IL-1 and TNF antagonists) exhibited an inhibitory effect on the progression of inflammatory cell infiltration toward the alveolar bone (75–77) and reduction of connective tissue attachment loss and bone resorption (68, 69). The effects of antiTNF therapy on periodontal status have also been reported in human trials (78–83), some of which described a beneficial effect of antiTNF therapy on the periodontal inflammatory indices (79, 81–83) and on the biochemical parameters of the periodontium (79, 81, 82) in patients with rheumatoid arthritis. A positive statistical correlation between the levels of TNF-a and the increase in clinical parameters of periodontitis (79, 82, 84, 85) was also found. On the other hand, in other studies it was observed that anti-TNF therapy without periodontal treatment had no significant effect on periodontitis (78, 80), although it seemed to lead to better results when used in conjunction with periodontal treatment (80). The integration of the results from human and nonhuman studies seems to indicate an improvement of periodontal inflammatory condition after treatment with BMs, more so if it is associated to periodontal treatment. Biologic drugs focusing on cytokine targets might moderate periapical tissue destruction and stimulate supporting tissue regeneration. TNF-a blockade can act directly by preventing the direct stimulatory effect of TNF-a on osteoclasts and through the reduction of receptor activator of nuclear factor kappa B ligand (86); furthermore, anti–TNF-a treatment could prevent the negative effect of TNF-a on osteoblast activity and differentiation. At the same time, by blocking the action of cytokines involved in inflammation, biologic drugs potentially permit the reactivation of infections and/or lead to an inadequate immune response to new pathogens requiring cell-mediated immunity, with a consequent increase of the risk of infections (87–89). The higher PAI score in patients taking immunomodulators may be related to the lack of treatment of AP. In other terms, biologic drugs do not have positive effects on AP in the absence of treatment, but they could influence the results of endodontic treatment when used in association with it. 392
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The fast radiographic healing of a tooth with a large periapical lesion after endodontic retreatment in association with the anti–TNFa treatment administered for a rheumatic syndrome was recently reported (90). In the present study the DMFT index was similar in both groups, in line with a previous report (35) but in contrast with other studies (32, 33). Among the limitations of the current study, there are the small sample size and the retrospective nature of the study that did not allow us to access more information than the one available. As a consequence, we were not able to establish a clear relationship between the period of time in which the IBDs were diagnosed with the time of appearance of the periapical lesions.
Conclusions When comparing healthy subjects with patients affected by IBDs and taking immunomodulators, women with IBDs exhibited overall worse periapical conditions. These results were even more significant when the subjects were on BMs, suggesting that a relationship between the female gender and AP in these patients needs to be further investigated. In general, AP appeared to be more common among patients with IBDs and on BMs but not in a significant way. In light of the relatively small sample size of this study and because of the growing indication for the use of BMs in many fields of medicine, it is important to gain more information on their interaction with endodontic treatment.
Acknowledgments The authors deny any conflicts of interest related to this study.
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49. Ørstavik D, Kerekes K, Eriksen HM. The periapical index: a scoring system for radiographic assessment of apical periodontitis. Endod Dent Traumatol 1986;2:20–34. 50. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159–74. 51. Ng YL, Mann V, Gulabivala K. A prospective study of the factors affecting outcomes of nonsurgical root canal treatment: part 1—periapical health. Int Endod J 2011;44: 583–609. 52. Cotti E, Schirru E, Acquas E, Usai P. An overview on biologic medications and their possible role in apical periodontitis. J Endod 2014;40:1902–11. 53. Carding S, Verbeke K, Vipond DT, et al. Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis 2015;26:26191. 54. Figueredo CM, Brito F, Barros FC, et al. Expression of cytokines in the gingival crevicular fluid and serum from patients with inflammatory bowel disease and untreated chronic periodontitis. J Periodontal Res 2011;46:141–6. 55. Noack B, G€orgens H, Hoffmann T, Schackert HK. CARD15 gene variants in aggressive periodontitis. J Clin Periodontol 2006;33:779–83. 56. Oz HS, Chen T, Ebersole JL. A model for chronic mucosal inflammation in IBD and periodontitis. Dig Dis Sci 2010;55:2194–202. 57. Tatakis DN, Guglielmoni P. HLA-B27 transgenic rats are susceptible to accelerated alveolar bone loss. J Periodontol 2000;71:1395–400. 58. Van Dyke TE, Dowell VR, Offenbacher S, et al. Potential role of microorganisms isolated from periodontal lesions in the pathogenesis of inflammatory bowel disease. Infect Immun 1986;53:671–7. 59. Kojima A, Nakano K, Wada K, et al. Infection of specific strains of Streptococcus mutans, oral bacteria, confers a risk of ulcerative colitis. Sci Rep 2012;2:1–11. 60. Marending M, Peters OA, Zehnder M. Factors affecting the outcome of orthograde root canal therapy in a general dentistry hospital practice. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99:119–24. 61. Azim AA, Griggs JA, Huang GT. The Tennessee study: factors affecting treatment outcome and healing time following nonsurgical root canal treatment. Int Endod J 2016;49:6–16. 62. Bender IB, Bender AB. Diabetes mellitus and the dental pulp. J Endod 2003;29: 383–9. 63. Segura-Egea JJ, Castellanos-Cosano L, Machuca G, et al. Diabetes mellitus, periapical inflammation and endodontic treatment outcome. Med Oral Patol Oral Cir Bucal 2012;17:e356–61. 64. Falk H, Hugoson A, Thorstensson H. Number of teeth, prevalence of caries and periapical lesions in insulin-dependent diabetics. Scand J Dent Res 1989;97:198–206. 65. de Sa AR, Moreira PR, Xavier GM, et al. Association of CD14, IL1B, IL6, IL10 and TNFA functional gene polymorphisms with symptomatic dental abscesses. Int Endod J 2007;40:563–72. 66. Morsani JM, Aminosharie A, Han YW, et al. Genetic predisposition to persistent apical periodontitis. J Endod 2011;37:455–9. 67. Kohsaka T, Kumazawa M, Yamasaki M, Nakamura H. Periapical lesions in rats with streptozotocin-induced diabetes. J Endod 1996;22:418–21. 68. Fouad A, Barry J, Russo J, et al. Periapical lesion progression with controlled microbial inoculation in a type I diabetic mouse model. J Endod 2002;28:8–16. 69. Oh WM, Hwang IN, Son HH, Hwang YC. Rapid periapical bone destruction during endodontic treatment of a patient with rheumatoid arthritis. J Endod 2008;34: 1261–3. 70. Smith RG, Patterson SS, El-Kafrawy AH. Histologic study of the effects of hydrocortisone on the apical periodontium of dogs. J Endod 1976;2:376–80. 71. Holland GR. Steroids reduce the periapical inflammatory and neural changes after pulpectomy. J Endod 1996;22:455–8. 72. Nobuhara WK, Carnes DL, Gilles JA. Anti-inflammatory effects of dexamethasone on periapical tissues following endodontic overinstrumentation. J Endod 1993;19: 501–7. 73. Metzger Z, Klein H, Klein A, Tagger M. Periapical lesion development in rats inhibited by dexamethasone. J Endod 2002;28:643–5. 74. Tepel J, Darwisch el Sawaf M, Hoppe W. Reaction of inflamed periapical tissue to intracanal medicaments and root canal sealers. Endod Dent Traumatol 1994;10: 233–8. 75. Assuma R, Oates T, Cochran D, et al. IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis. J Immunol 1998;160:403–9. 76. Delima AJ, Oates T, Assuma R, et al. Soluble antagonists to interleukin-1 (IL-1) and tumor necrosis factor (TNF) inhibits loss of tissue attachment in experimental periodontitis. J Clin Periodontol 2001;28:233–40. 77. Graves DT, Delima AJ, Assuma R, et al. Interleukin-1 and tumor necrosis factor antagonists inhibit the progression of inflammatory cell infiltration toward alveolar bone in experimental periodontitis. J Periodontol 1998;69: 1419–25. 78. Savioli C, Ribeiro AC, Fabri GM, et al. Persistent periodontal disease hampers antitumor necrosis factor treatment response in rheumatoid arthritis. J Clin Rheumatol 2012;18:180–4.
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Prevalence of Apical Periodontitis in Patients with Inflammatory Bowel Diseases: A Retrospective Clinical Study Vanessa Piras, DDS,* Paolo Usai, MD,† Silvia Mezzena, DDS,* Marta Susnik, DDS,* Francesca Ideo, DDS,* Elia Schirru, DDS,‡ and Elisabetta Cotti, DDS, MS* Abstract Aim: We evaluated the prevalence of apical periodontitis (AP) and the oral health status in patients with inflammatory bowel diseases (IBDs) treated with immunomodulators, with particular attention to biologic medications (BMs). Methods: One hundred ten patients, 49 men and 61 women (average age, 46 13.8 years), from the Gastroenterology Unit of the University Hospital with IBDs who were treated with BMs or corticosteroids were included in the study. One hundred ten patients who registered for a dental check-up at the Dental Clinic were matched for age, sex, and physical characteristics with the study group without systemic diseases and not taking medications who were the control. Patients underwent a complete oral, dental, and radiographic examination. Decayed, missing, and filled teeth and periapical index score indexes were recorded. Student t test, c2, and MannWhitney U test were used as appropriate. Results: The prevalence of AP was 64% in IBD patients and 59% in the control; according to the gender-stratified analysis, the difference was not significant among the male groups, whereas the number of teeth with AP was significantly higher in female patients with IBDs than in the controls (P # .05). The prevalence of AP in patients treated with BMs was 65%; women showed 69% higher risk for AP and presented a significantly higher number of teeth with AP (P # .05). Decayed, missing, and filled teeth index was similar in both groups, whereas patients with IBDs had a higher periapical index score than the controls. Conclusions: Women with IBDs and taking immunomodulators had a higher prevalence of AP. All patients with IBDs had larger lesions than healthy subjects. These data emphasize the influence of the status of the immune system in the onset of AP and the need for further studies to confirm these findings. (J Endod 2017;43:389–394)
Key Words Apical periodontitis, biologic medications, inflammatory bowel diseases
I
nflammatory bowel Significance diseases (IBDs) are The development and evolution of apical periodonmultifactorial, idiopathic, titis in patients affected by autoimmune diseases chronic inflammatory disand in treatment with the new immunomodulators orders characterized by need to be considered carefully. diffuse inflammation of the intestinal mucosa. They are associated with dysregulation and inappropriate response of the intestinal mucosal immune system to otherwise innocuous luminal antigens in a genetically susceptible host (1, 2). Crohn’s disease (CD) and ulcerative colitis (UC) are 2 main phenotypes of IBD (3–5). Genetic predisposition (6–9) and deficiencies in the innate immune response can be linked to the development of IBDs. The pathogenesis of IBDs is the result of an imbalance of proinflammatory and antiinflammatory factors (10, 11). UC is characterized by an upregulation of interleukin (IL)-5 and can be considered as a type 2 immune disease, whereas CD exhibits high levels of interferon-g, IL-12, and tumor necrosis factor (TNF) and is classified as a type 1 immune disease prototype (12). First-line treatment (13–15) for IBDs has been centered on immunosuppressive therapy such as disease-modifying anti-inflammatory drugs or corticosteroids (16). Nonsteroidal anti-inflammatory drugs are used to relieve pain and inflammation and treat the symptoms of extraintestinal manifestations of IBDs (arthralgia, arthritis) (17–19). Patients who have not responded to standard therapies are currently being treated with biologic medications (BM), which are predominantly recombinant human proteins with immunoregulatory effects (20–28). Their target is mainly the modulation of proinflammatory cytokines. Anti-TNF agents have been reported to achieve remission of the disease, tapering of glucocorticoids (26, 29), and healing of the mucosa (30). Oral manifestations of IBDs can be found in 4%–16% of patients and include persistent soft tissue swellings, edema of the mucosa, linear ulceration, angular cheilitis, and granulomatous gingivitis (31). Furthermore, IBD patients seem to have increased prevalence of caries and periodontitis (32–38). Apical periodontitis (AP) is a chronic inflammatory disorder of the periradicular tissues caused by an infection of endodontic origin. It is the consequence of a dynamic encounter between root canal microbes and host defenses that results in a local inflam-
From the *Department of Conservative Dentistry and Endodontics, School of Dentistry, and †Department of Gastroenterology, School of Medicine, University of Cagliari, Cagliari, Italy; and ‡Department of Endodontology, Kings College Dental Institute, London, United Kingdom. Address requests for reprints to Dr Elisabetta Cotti, Department of Conservative Dentistry and Endodontics, University of Cagliari Italy, VIA ROMA 149, 09124 Cagliari, Italy. E-mail address: [email protected] 0099-2399/$ - see front matter Copyright ª 2016 American Association of Endodontists. http://dx.doi.org/10.1016/j.joen.2016.11.004
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Clinical Research mation, resorption of hard tissues, and destruction of other periapical tissues driven by complex interactions between immune-inflammatory cells and soluble mediators (39, 40). Prevalence of AP increases with age and varies from 33% to 62% (41). Because no studies to date have investigated the association of IBDs with AP, the purpose of this investigation was to evaluate the prevalence of AP and the oral health status in patients with IBDs, with particular attention to the influence of BMs on AP.
Materials and Methods Medical records of 110 patients affected by IBDs who were referred to the University Dental Clinic for a routine dental evaluation during the period of June 2012–July 2015 were retrospectively studied; data extrapolated were compared with those from 110 healthy patients not subjected to any pharmacologic therapy who visited at the Dental Clinic in the same period. The study was approved by the Institutional Ethics Committee and was in accordance with the Helsinki Declaration of 1975 (as revised in 2000). All participants gave their informed consent before inclusion in the study.
Selection of Cases The patients with gastrointestinal (GI) chronic immune diseases, CD, or UC were recruited for this retrospective study. The eligibility criteria for inclusion were the following: 1. 2. 3. 4.
Male and female patients Age range 18–70 years Affected by a GI chronic immune disease Taking corticosteroids or BM for at least 6 months for the GI disease Exclusion criteria included the following:
1. Patients presenting with other systemic pathologies 2. Patients taking more than 1 medication for the major pathology 3. Patients who did not allow their data to be used A total of 110 records from patients with IBD, 49 men and 61 women (average age, 46 13.8 years), were recruited; 74 patients in treatment with BMs and 36 patients in treatment with corticosteroids who agreed and met the inclusion/exclusion criteria constituted the study group. All these individuals were outpatients attending the Department of Gastroenterology at D. Casula Hospital of the University of Cagliari, Italy. In IBD patients the average period of time in which the disease was present was 12 7.5 years. Diagnosis of CD and UC were performed according to the international investigational protocols (42–46). An additional 110 subjects, 53 men and 57 women (average age, 41 13.1 years), who reported no history of IBD or any clinical sign of ongoing systemic diseases, were matched for age, gender, and socioeconomic status (education, occupation, income), and who also met the inclusion criteria constituted the control group. Patients in the control group were randomly recruited in this retrospective study among the patients from the same health district seeking routine dental examination at the same Dental Clinic for the first time.
Clinical Data Collection and Radiographic Examination All medical records comprised a questionnaire covering demographic data including age, gender, medical history, and medications taken. The medical history records were focused on the collection of relevant information regarding the major IBD disease, the time of onset of the disease, and the previous and current medications taken to treat the disease. A written informed consent for the dental examination, the panoramic radiograph, the addi390
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tional periapical radiographs, and the use of the clinical data were included in all medical records. The medical record review was used to collect the data. The following parameters were assessed: number of teeth in the dental arches, presence of caries, presence of conservative restorations, presence of extensive restorations (conservative/prosthetic), presence of endodontic treatment, presence of apical periodontitis, evaluation of periodontal probing depth, and presence of lesions in the soft tissues (sinus tracts/abscesses/other). The teeth were examined according to the decayed, missing, filled teeth (DMFT) index by using the World Health Organization criteria (47). The evaluation of the panoramic radiographs (used as initial screening) and of all of the selective intraoral radiographs (taken in upper anterior teeth, when scarcely visible, in all teeth that presented restorations, prosthetic restorations, AP, or suspected AP in the panoramic radiograph) available in the medical records were used for the assessment of the periapical status.
Acquisition of Data Medical history, diagnostic, and treatment information for each patient were entered on a collection form and coded for computer entry. At the initial visit, after the evaluation of the panoramic radiograph and the clinical examination, standardized periapical radiographs were taken. Conventional radiographs were obtained by using a film holder for paralleling technique. Exposure times and kilovoltage were adjusted according to the film manufacturer’s instructions. The periapical radiographs were scanned, saved in JPEG format, and transferred to the Image J software (version 1.41; National Institutes of Health, Bethesda, MD) for measurement and recording of the results. The plug-in application TurboReg (Biomedical Imaging Group, Swiss Federal Institute of Technology, Lausanne, VD, Switzerland) was used to mathematically minimize any dimensional changes that might have been incorporated into the preoperative or postoperative radiographs as a result of angulation differences to the x-ray central beam at the time of image acquisition (48). The periapical status was assessed by using the periapical index score (PAI) (49) by 2 trained and calibrated endodontists (weighted kappa values, k = 0.8) (50). For multirooted teeth, the highest of the PAI scores given to the individual roots was used. If the 2 examiners did not agree, the highest of their scores was assigned. The quality of coronal restorations and root canal treatments was assessed by the same 2 examiners on the basis of the criteria described by Ng et al (51). When 1 of the components was not satisfactory, the entire tooth was judged as inadequate. Statistical Analysis The prevalence of AP was evaluated on the total number of individuals and the total number of teeth. Statistical analysis was also differentiated by sex to investigate the possible confounding role of gender on the risk of AP. Descriptive analysis was performed, and the differences between groups were evaluated with Student t test for normal distributed variables, c2, or Mann-Whitney U test as appropriate. A further analysis was performed to assess possible differences between patients treated with BMs and controls; P value # .05 was considered statistically significant. STATA version 13 (STATA Corp, College Station, TX) was used.
Results The prevalence of AP was 64% in the IBD group and 59% in the control (Table 1) (P > .05); the same happened with the number of teeth with AP, which was higher in patients with IBDs compared with the controls (P > .05). Gender-stratified analyses showed a higher JOE — Volume 43, Number 3, March 2017
Clinical Research TABLE 1. Prevalence of AP in IBD and Control Groups and Gender Stratification Overall IBD Control P value Female IBD Control P value Male IBD Control P value
Subjects with AP
Teeth with AP
No. of teeth
DMFT
PAI
64% 59% .489
1 [0–2], 1.63 (2.0) 1 [0–2], 1.16 (1.4) .098*
25 (6.1) 28 (3.5) .0004
9.1 (4.6) 9.2 (5.1) .93
3.9 (1.0) 2.8 (1.1) .0001
59% 51% .374
1 [0–3], 1.83 (2.4) 1 [0–1], 0.98 (1.4) .042*
25 (5.7) 28 (2.9) .0057
10 (4.8) 8.3 (4.3) .046
3.8 (0.97) 8.3 (4.3) .0001
69% 68% .874
1 [0–2], 1.38 (1.2) 1 [0–2], 1.35 (1.4) .58*
25 (6.5) 27 (4.0) .025
8.0 (4.0) 10.1 (5.6) .034
3.9 (1.0) 3.1 (1.1) .0026
Results are presented as percentage frequency, median [I–III quartile], mean (standard deviation). *Wilcoxon rank test.
risk for AP in IBD women compared with the controls (odds ratio [OR], 1.44; 95% confidence interval [CI], 0.86–2.39 and OR, 1.03; 95% CI, 0.61–1.74, respectively; P > .05). All the differences described above were not significant (Table 1). However, women with IBDs had a significantly higher number of teeth with AP (P < .05) (Table 1). Men with IBDs had an equal risk of being affected by AP (OR, 1.07; 95% CI, 0.44–2.48) and no difference in the number of teeth with AP (P > .05) compared with the controls (Table 1). The prevalence of AP among IBD patients taking BMs was not significantly higher than in controls (P > .05), whereas the number of teeth with AP was higher in patients taking BMs (P = .05) (Table 2). Women with IBDs and treated with BMs showed 69% higher risk for AP (OR, 1.69; 95% CI, 0.68–3.9) but not statistically significant (P > .05) (Table 2), yet they exhibited a significantly higher number of teeth with AP (P < .05). Among IBD men there were no differences between the groups in the number of subjects and teeth with AP (P > .05) (Table 2). IBD patients exhibited a significantly higher PAI index when compared with the controls (3.9 vs 2.8; P < .05) and a similar mean DMFT score (9.1 vs. 9.2; P > .05) (Table 1). When divided by gender, IBD women showed a higher DMFT score than controls (P < .05) (Table 1), whereas an opposite trend was evident among men (P < .05) (Table 1). These results were confirmed in BMs subgroup (Table 2). The quality of root canal treatment and coronal restoration of endodontically treated teeth with AP was judged adequate in 63% of teeth in the IBD group and in 68% of teeth in the control group.
Discussion We investigated the prevalence of AP and the oral health status in patients affected by a category of autoimmune diseases (IBDs) and taking immunomodulators, with particular attention to the possible effects of the newly used biologic immune modulators on AP (52). When the patients in the study group received the dental and endodontic evaluation, they had been diagnosed with IBD for an average of 12 7.5 years. We observed that the technical quality of root canal treatment and coronal restorations in the teeth with AP that had been previously treated received a similar score in IBD patients and in controls. On one hand, we found that AP was not significantly prevalent among patients with IBDs; on the other hand, we found that women with IBDs tend to have a higher number of periapical lesions, and when treated with biologics, they are at even higher risk for AP compared with the healthy controls. There is growing evidence that dysbiosis of the gut microbiota contributes to the development of both intestinal and extraintestinal disorders (53). Consequently, IBDs might represent an independent risk factor for the development of chronic oral diseases (54–57), and conversely, the presence of dental diseases may influence the development of IBDs (58, 59). It has already been assessed how the integrity of the nonspecific immune system is one of the key factors in the favorable outcome of endodontic treatment (60) and in the healing time of AP (61), and studies have shown a higher prevalence of AP in diabetic patients (62, 63), with women with long-standing type 1 diabetes exhibiting more root-filled teeth with periapical lesions (64).
TABLE 2. Prevalence of AP in BM and Control Groups and Gender Stratification Overall BM Control P value Female BM Control P value Male BM Control P value
Subjects with AP
Teeth with AP
No. of teeth
DMFT
PAI
65% 59% .43
1 [0–2], 1.66 (1.98) 1 [0–2], 1.16 (1.4) .050*
25 (6.3) 28 (3.5) .0001
9.0 (4.9) 9.2 (5.1) .77
3.8 (1.0) 2.8 (1.1) .0001
63% 51% .26
1 [0–4], 2.0 (2.4) 1 [0–1], 0.98 (1.4) .015*
25 (6.2) 28 (2.9) .0007
10.5 (5.3) 8.3 (4.3) .034
3.9 (0.99) 2.5 (0.87) .0001
67% 68% .89
1 [0–2], 1.35 (1.3) 1 [0–2], 1.35 (1.4) .72*
25 (6.6) 27 (4.0) .033
7.6 (4.2) 10.2 (5.7) .022
3.7 (1.0) 3.1 (1.1) .025
Results are presented as percentage frequency, median [I–III quartile], mean (standard deviation). *Wilcoxon rank test.
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Clinical Research The different behavior of AP, such as the presence of clinical symptoms (65), and the increased susceptibility to persistent AP (66) are also influenced by the genetic polymorphisms associated with the expression of some cytokines. All these consecutive observations keep the focus on the impact that impaired or modulated immune system may have on the onset, evolution, and healing of infections of endodontic origin. Another interesting result comes from the size of AP; the average PAI score was higher in IBD patients treated with immunomodulators than in the controls. This observation would confirm that a chronic systemic autoimmune inflammatory disorder and/or the use of the immunomodulators may influence the periapical status of the compromised teeth. These observations are coherent with results from animal studies that have shown that immune compromised rats and diabetic NOD mice developed a more severe response to pulp infection and larger periradicular lesions (67, 68). However, there is still limited information regarding the effects of IBDs and of the different types of immunomodulators on the development of AP. An unusually fast development of a periapical lesion in a patient affected by rheumatoid arthritis taking azathioprine and corticosteroids was recently reported (69). The reduction of periapical inflammation after the systemic, intramuscular, or local administration of corticosteroids was also described (70–73), whereas opposite results were obtained when a combination of corticosteroids and antibiotic was used as an intracanal medication (74). The data in the literature on BMs and oral infections are mostly limited to periodontitis, which represents a similar model for etiology and pathogenesis to AP. In a primate model of experimental periodontitis, the administration of BMs (IL-1 and TNF antagonists) exhibited an inhibitory effect on the progression of inflammatory cell infiltration toward the alveolar bone (75–77) and reduction of connective tissue attachment loss and bone resorption (68, 69). The effects of antiTNF therapy on periodontal status have also been reported in human trials (78–83), some of which described a beneficial effect of antiTNF therapy on the periodontal inflammatory indices (79, 81–83) and on the biochemical parameters of the periodontium (79, 81, 82) in patients with rheumatoid arthritis. A positive statistical correlation between the levels of TNF-a and the increase in clinical parameters of periodontitis (79, 82, 84, 85) was also found. On the other hand, in other studies it was observed that anti-TNF therapy without periodontal treatment had no significant effect on periodontitis (78, 80), although it seemed to lead to better results when used in conjunction with periodontal treatment (80). The integration of the results from human and nonhuman studies seems to indicate an improvement of periodontal inflammatory condition after treatment with BMs, more so if it is associated to periodontal treatment. Biologic drugs focusing on cytokine targets might moderate periapical tissue destruction and stimulate supporting tissue regeneration. TNF-a blockade can act directly by preventing the direct stimulatory effect of TNF-a on osteoclasts and through the reduction of receptor activator of nuclear factor kappa B ligand (86); furthermore, anti–TNF-a treatment could prevent the negative effect of TNF-a on osteoblast activity and differentiation. At the same time, by blocking the action of cytokines involved in inflammation, biologic drugs potentially permit the reactivation of infections and/or lead to an inadequate immune response to new pathogens requiring cell-mediated immunity, with a consequent increase of the risk of infections (87–89). The higher PAI score in patients taking immunomodulators may be related to the lack of treatment of AP. In other terms, biologic drugs do not have positive effects on AP in the absence of treatment, but they could influence the results of endodontic treatment when used in association with it. 392
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The fast radiographic healing of a tooth with a large periapical lesion after endodontic retreatment in association with the anti–TNFa treatment administered for a rheumatic syndrome was recently reported (90). In the present study the DMFT index was similar in both groups, in line with a previous report (35) but in contrast with other studies (32, 33). Among the limitations of the current study, there are the small sample size and the retrospective nature of the study that did not allow us to access more information than the one available. As a consequence, we were not able to establish a clear relationship between the period of time in which the IBDs were diagnosed with the time of appearance of the periapical lesions.
Conclusions When comparing healthy subjects with patients affected by IBDs and taking immunomodulators, women with IBDs exhibited overall worse periapical conditions. These results were even more significant when the subjects were on BMs, suggesting that a relationship between the female gender and AP in these patients needs to be further investigated. In general, AP appeared to be more common among patients with IBDs and on BMs but not in a significant way. In light of the relatively small sample size of this study and because of the growing indication for the use of BMs in many fields of medicine, it is important to gain more information on their interaction with endodontic treatment.
Acknowledgments The authors deny any conflicts of interest related to this study.
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