Role of tumor necrosis factor-alpha in pathogenesis of recurrent aphthous stomatitis: A systematic review and meta-analysis

Document Type : Review Article(s)


1 Assistant Professor, Department of Oral Medicine, School of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran

2 Assistant Professor, Department of Restorative Dentistry, School of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran

3 Student of Dentistry, Department of Oral Medicine, School of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran



BACKGROUND AND AIM: Recurrent aphthous stomatitis (RAS) is a lesion of the oral cavity with an unknown etiology. Several studies have been performed on the role of tumor necrosis factor-alpha (TNF-α) in RAS. The main purpose of this paper was to review TNF-α level and its gene polymorphism in patients with RAS, the factors influencing the production of TNF-α, and its role in RAS development.
METHODS: In this review study, all articles containing English abstract were searched in the PubMed, Cochrane Library, and Scopus databases from January 2000 to December 2019. The searches were done using the Medical Subject Heading (MESH) terms and keywords of "recurrent aphthous stomatitis" or "recurrent aphthous ulcers" or "recurrent oral ulcers" and “tumor necrosis factor-alpha” or “TNF-α”. The data for gene polymorphism were analyzed using Comprehensive Meta-Analysis (CMA) software. Regarding the heterogeneity of studies, the random effects model was used. Cochran’s Q and I2 tests were used to evaluate statistical heterogeneity between the studies.
RESULTS: Amongst the 619 articles obtained in the first stage of our search of database, 21 articles which were fitted to our study based on the entry/exit criteria were selected in the review. According to this meta-analysis, recessive model of TNF-α -308 G/A had protective effects for RAS [odds ratio (OR) = 0.392, 95% confidence interval (CI) = 0.145-1.061, P = 0.045].
CONCLUSION: The results showed the important role of TNF-α in RAS development. There are numerous factors involved in producing this cytokine. Identifying TNF-α production pathway and its effects in RAS formation is significant in developing new prevention and treatment methods.


Scully C, Felix DH. Oral medicine--update for the dental practitioner. Aphthous and other common ulcers. Br Dent J 2005; 199(5): 259-64.
Slebioda Z, Szponar E, Kowalska A. Etiopathogenesis of recurrent aphthous stomatitis and the role of immunologic
aspects: Literature review. Arch Immunol Ther Exp (Warsz) 2014; 62(3): 205-15.
Akintoye SO, Greenberg MS. Recurrent aphthous stomatitis. Dent Clin North Am 2014; 58(2): 281-97.
Motahari P. Evaluation of antioxidant-oxidant status of saliva in recurrent aphthous stomatitis: A systematic review. J Oral Health Oral Epidemiol 2020; 9(2): 60-4.
Bhosale SS, Rajput BS, Takkar H, Bhagat SV, Vagger RM, Shaikh MIK. Establishment of role of IL-2, IL-10 and IL-12 in patients with recurrent aphthous stomatitis-a clinical study. J Contemp Dent Pract 2018; 19(10): 1242-5.
Wei W, Sun Q, Deng Y, Wang Y, Du G, Song C, et al. Mixed and inhomogeneous expression profile of Th1/Th2 related cytokines detected by cytometric bead array in the saliva of patients with oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol 2018; 126(2): 142-51.
Hegde S, Ajila V, Babu S, Kumari S, Ullal H, Madiyal A. Evaluation of salivary tumour necrosis factor-alpha in patients with recurrent aphthous stomatitis. Eur Oral Res 2018; 52(3): 157-61.
Chaudhuri K, Nair KK, Ashok L. Salivary levels of TNF-alpha in patients with recurrent aphthous stomatitis: A cross-sectional study. J Dent Res Dent Clin Dent Prospects 2018; 12(1): 45-8.
Avci E, Akarslan ZZ, Erten H, Coskun-Cevher S. Oxidative stress and cellular immunity in patients with recurrent aphthous ulcers. Braz J Med Biol Res 2014; 47(5): 355-60.
10. Eguia-del VA, Martinez-Conde-Llamosas R, Lopez-Vicente J, Uribarri-Etxebarria A, Aguirre-Urizar JM. Salivary levels of Tumour Necrosis Factor-alpha in patients with recurrent aphthous stomatitis. Med Oral Patol Oral Cir Bucal 2011; 16(1): e33-e36.
11. Lewkowicz N, Kur B, Kurnatowska A, Tchorzewski H, Lewkowicz P. Expression of Th1/Th2/Th3/Th17-related genes in recurrent aphthous ulcers. Arch Immunol Ther Exp (Warsz) 2011; 59(5): 399-406.
12. Borra RC, de Mesquita BF, de Andrade LM, Villanova FE, Andrade PM. Toll-like receptor activity in recurrent aphthous ulceration. J Oral Pathol Med 2009; 38(3): 289-98.
13. Albanidou-Farmaki E, Markopoulos AK, Kalogerakou F, Antoniades DZ. Detection, enumeration and characterization of T helper cells secreting type 1 and type 2 cytokines in patients with recurrent aphthous stomatitis. Tohoku J Exp Med 2007; 212(2): 101-5.
14. Dalghous AM, Freysdottir J, Fortune F. Expression of cytokines, chemokines, and chemokine receptors in oral ulcers of patients with Behcet's disease (BD) and recurrent aphthous stomatitis is Th1-associated, although Th2-association is also observed in patients with BD. Scand J Rheumatol 2006; 35(6): 472-5.
15. Boras VV, Lukac J, Brailo V, Picek P, Kordic D, Zilic IA. Salivary interleukin-6 and tumor necrosis factor-alpha in patients with recurrent aphthous ulceration. J Oral Pathol Med 2006; 35(4): 241-3.
16. Lewkowicz N, Lewkowicz P, Banasik M, Kurnatowska A, Tchorzewski H. Predominance of Type 1 cytokines and decreased number of CD4(+)CD25(+high) T regulatory cells in peripheral blood of patients with recurrent aphthous ulcerations. Immunol Lett 2005; 99(1): 57-62.
17. Sun A, Chia JS, Chang YF, Chiang CP. Levamisole and Chinese medicinal herbs can modulate the serum interleukin-6 level in patients with recurrent aphthous ulcerations. J Oral Pathol Med 2003; 32(4): 206-14.
18. Yun-Qiu Z. The relationship between recurrent oral ulcer andserum TNF-α and TGF-β levels. Medical Journal of Wuhan University 2001; 22(3):238.
19. Natah SS, Hayrinen-Immonen R, Hietanen J, Malmstrom M, Konttinen YT. Immunolocalization of tumor necrosis factor-alpha expressing cells in recurrent aphthous ulcer lesions (RAU). J Oral Pathol Med 2000; 29(1): 19-25.
20. Sun M, Fu SM, Dong GY, Wu D, Wang GX, Wu Y. Inflammatory factors gene polymorphism in recurrent oral ulceration. J Oral Pathol Med 2013; 42(7): 528-34.
21. Guimaraes AL, Correia-Silva JF, Sa AR, Victoria JM, Diniz MG, Costa FO, et al. Investigation of functional gene polymorphisms IL-1beta, IL-6, IL-10 and TNF-alpha in individuals with recurrent aphthous stomatitis. Arch Oral Biol 2007; 52(3): 268-72.
22. Bazrafshani MR, Hajeer AH, Ollier WE, Thornhill MH. Recurrent aphthous stomatitis and gene polymorphisms for the inflammatory markers TNF-alpha, TNF-beta and the vitamin D receptor: No association detected. Oral Dis 2002; 8(6): 303-7.
23. Lewkowicz N, Lewkowicz P, Dzitko K, Kur B, Tarkowski M, Kurnatowska A, et al. Dysfunction of CD4+CD25high T regulatory cells in patients with recurrent aphthous stomatitis. J Oral Pathol Med 2008; 37(8): 454-61.
24. Al-Samadi A, Drozd A, Salem A, Hietanen J, Hayrinen-Immonen R, Konttinen YT. Epithelial Cell Apoptosis in Recurrent Aphthous Ulcers. J Dent Res 2015; 94(7): 928-35.
25. Al-Samadi A, Salem A, Ainola M, Hietanen J, Hayrinen-Immonen R, Konttinen YT. Increased beta 2 defensin in recurrent aphthous ulcer. Oral Dis 2015; 21(3): 292-8.
26. Al-Samadi A, Kouri VP, Salem A, Ainola M, Kaivosoja E, Barreto G, et al. IL-17C and its receptor IL-17RA/IL-17RE identify human oral epithelial cell as an inflammatory cell in recurrent aphthous ulcer. J Oral Pathol Med 2014; 43(2): 117-24.
27. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6(7): e1000097.
28. Boudin F, Nie JY, Bartlett JC, Grad R, Pluye P, Dawes M. Combining classifiers for robust PICO element detection. BMC Med Inform Decis Mak 2010; 10: 29.
29. Munn Z, Tufanaru C, Aromataris E. JBI's systematic reviews: Data extraction and synthesis. Am J Nurs 2014; 114(7): 49-54.
30. Thornhill MH, Baccaglini L, Theaker E, Pemberton MN. A randomized, double-blind, placebo-controlled trial of pentoxifylline for the treatment of recurrent aphthous stomatitis. Arch Dermatol 2007; 143(4): 463-70.
31. Serrano NC, Millan P, Paez MC. Non-HLA associations with autoimmune diseases. Autoimmun Rev 2006; 5(3): 209-14.
32. Hajeer AH, Hutchinson IV. TNF-alpha gene polymorphism: Clinical and biological implications. Microsc Res Tech 2000; 50(3): 216-28.
33. Helmig S, Aliahmadi N, Stephan P, Dohrel J, Schneider J. TNF-alpha -308 genotypes are associated with TNF-alpha and TGF-beta(1) mRNA expression in blood leucocytes of humans. Cytokine 2011; 53(3): 306-10.