Review paper
Recurrent aphthous stomatitis: genetic aspects of etiology

Introduction

Recurrent aphthous stomatitis (RAS; recurrent aphthous ulcers – RAU; canker sores) belongs to a group of chronic, inflammatory, ulcerative diseases of the oral mucosa [1-4]. The condition was initially described by a superb surgeon of Polish origin, Johann von Mikulicz-Radecki, in 1898 [5]. To honor the author, a great professor and scientist, a pioneer in many surgical techniques, small aphthae are traditionally called the Mikulicz’s aphthae [5, 6]. Multifactorial etiopathogenesis of RAS remains still not fully understood. The genetic background and the disturbed immunologic mechanisms of this condition have not been clearly defined so far [7-10]. In the course of RAS, a recurrent onset of single or multiple painful erosions and ulcers in various regions of the oral mucosa is observed. These eruptions are surrounded by erythematous halo, while the other regions of the oral mucosa remain unchanged. Most common locations of the lesions include the areas covered with non-keratinized oral mucosa: the lips, cheeks, floor and vestibule of the mouth, palatal arches and soft palate [2, 7, 8, 10, 11]. Severe pain, which often disturbs speaking and swallowing, may accompany the development of the lesions. The treatment of the disease is not very effective and mainly symptomatic. Aphthous ulcers occur as a result of enhanced immunologic response and the activation of pro-inflammatory cy­tokines’ cascade, directed against the selected regions of the oral mucosa [12, 13]. Histologic observations of the oral mucosa affected by RAS revealed the presence of massive, leukocytic infiltration, which evolves with time. In the initial stage of the disease, before the ulcer is formed, monocytes, lymphocytes (mainly T type) with single mast and plasmatic cells accumulate under the basal layer. In the advanced stages, polynuclear lymphocytes dominate in the center of the ulcer, while the massive infiltrate of mononuclear cells surrounds the aphtha [14, 15]. Considering the clinical features, three main types of recurrent aphthous stomatitis can be defined: minor aphthae (Mikulicz’s aphthae; MiRAS), major aphthae (Sutton’s aphthae; MaRAS) and herpetiform aphthae (HeRAS) [1, 2, 16].

The most common type of RAS is the minor aphtha, which can be described as an erosion smaller than 1 cm in diameter, surrounded by erythematous halo. It heals with no scar formation and lasts no longer than 2 weeks. Mikulicz’s aphtha on the upper lip in a female patient of the Department of Oral Mucosa Diseases, Poznan University of Medical Sciences is presented in Figure 1.

Sutton’s aphthae are typical ulcers – they are observed less frequently than MiRAS, larger and extend deeper. They are very painful and may significantly disturb speaking and swallowing. Lesions heal slowly (they may last up to 1 month) and very often with scaring. Herpetiform aphthae are very small and multiple – up to 100 lesions may be observed simultaneously during one episode of the disease. In no type of aphthae, vesicles or gingivitis – typical symptoms of viral infections – can be observed

[1-3, 16]. The most crucial clinical signs of aphthae are presented in Table 1.

Recurrent aphthous stomatitis may be also one of the symptoms of the Behçet’s syndrome – a systemic, inflammatory disease, where, apart from oral and genital lesions, various general symptoms may occur. They include anterior or posterior uveitis, retinal vasculitis, erythema nodosum, cutaneous vasculitis and arthralgia and less commonly – dysfunction of the gastrointestinal tract, nervous system and kidneys [9, 17-20].

The occurrence of RAS varies in patients’ populations depending on their ethnic origin and on the diagnostic criteria system accepted in different research centers. The occurrence of aphthae in general population ranges between 5% and 20% [2, 7-9]. In two independent North-American studies recurrent aphthous stomatitis directly during the dental examination was observed in 0.89% and in 1.03% of randomly chosen subjects, respectively [21, 22], while in the cross-sectional study in Turkey, aphthae were observed in 1.2% of the examined patients [23]. In Reichart study performed on 1997 in Germany, among 655 volunteers aged 35-44 years the frequency of the disease directly during the examination was described as 1.4%, while it reached 18.3% when the data from the patient’s history were also included (RAS in the history) [24]. Similar results were observed by Gorska in a study from 1994, performed on 1537 high-school students from Warsaw, Poland. Recurrent aphthae during the examination appeared in 2% of students, while the RAS occurrence increased up to 27.3% after the inclusion of the past episodes of the disease from the history [25]. In the

10-year retrospective observations of the Department of Oral Mucosa Diseases, Poznan University of Medical Sciences, subjects with RAS accounted for 7.6% of a total number of admitted patients [26].

Many epidemiologic studies and our own observations confirmed the higher incidence of RAS in people with a higher socio-economic status. Also females seem to be at a higher risk of the disease development in comparison to males [4, 21, 22, 26]. In the North-American population, aphthae appear 3 times more often in Caucasians than in Afro-Americans, the condition affects also more often non-smokers in comparison to smokers [21, 22]. Aphthae may appear for the first time in childhood or at later life stages. The second life decade is considered as a peak period of the RAS occurrence. The severity and frequency of the episodes vary on a case-by-case basis, however, it usually decreases with age [2, 21, 26].

Genetic background of recurrent aphthous stomatitis

The etiology of recurrent aphthous stomatitis still remains not clearly understood. The possible trigger factors include immunologic and hormonal disturbances, genetic background, infections, food allergies, vitamin and microelement deficiencies, gastrointestinal diseases (celiac disease, Crohn’s disease, ulcerative colitis), me­chanical injuries and stress [7, 8, 17, 27, 28].

The role of genetic predisposition in recurrent aphthous stomatitis was for the first time suggested by

Mil­ler et al. in 1977 and Ship in 1965, who assumed the au­tosomal recessive or multigene mode of inheritance with the modulating influence of the environment [29, 30].

In the epidemiologic studies, the positive family history of the disease has been reported in 24% to 46% of RAS subjects [1, 7]. According to Safadi, a positive family history was found in 66.4% of the examined 684 Jordanian patients with RAS [31]. The presence of aphthae in parents influences significantly the risk of RAS development and the course of the disease in their offspring. The risk of RAS in a child with both parents with aphthae reaches 90%, while in children with healthy parents it was estimated at 20% [8]. People with a positive family history are prone to develop a more severe type of the disease with more frequent recurrences than the subjects with no history of RAS in the family [29, 30]. Family and twin studies confirmed the role of genetic predispositions in the development of RAS [31, 32]. Moreover, similarly to Behçet’s syndrome, the risk of the disease occurrence is higher in monozygotic twins than in dizygotic ones

[31, 32]. An interesting case of monozygotic twins with RAS was presented by Kobayashi et al., while Yilmaz and Cimen described the disease occurrence in 4 members of the same family [19, 32].

The genetic risk factors which may determine the individual susceptibility to recurrent aphthous stomatitis include various DNA polymorphisms distributed in the human genome. A special attention should be paid to the alterations in the metabolism of cytokines, which include: interleukins (IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12), interferon  (IFN-) and tumour necrosis factor- (TNF-)

[12, 35-38], serotonin transporter gene and endothelial nitric oxide synthase gene [39-41]. The analysis of the expression of selected genes in the oral cavity in patients with RAS was performed by Bun~o et al. The elevated concentration of mRNA corresponding with IL-2, IFN- and TNF- and the decreased mRNA level corresponding with IL-10 was detected in the examined subjects with aphthae in comparison to healthy controls [35]. The results of the observations on the role of DNA polymorphisms in RAS and Behçet’s disease development using the genetic associations presented in Table 2 still remains ambiguous and equivocal.

Akman et al. observed a higher frequency of TNF--1031C allele, corresponding with the increased number of mononuclear cells that produce IFN- and TNF- in peripheral blood of patients with Behçet’s syndrome in comparison to healthy controls [12]. In Guimarães et al.’s study, a correlation between the TNF-α gene polymorphism and the increased RAS risk was observed, which remains consistent with previously cited Bun~o et al.’s results [35, 36]. The elevated concentration of the described proinflammatory cytokines supports the thesis that the Th1-type cellular immune response plays a crucial role in the development of RAS and Behçet’s syndrome. In their further studies Guimarães et al. observed also a correlation between one of the IL-1 gene polymorphisms, related with the enhanced IL-1 production, and the risk of RAS development [36]. That sort of association was not detected for IL-6 and IL-10 genes’ polymorphisms [37]. Also Akman

et al. investigated the role of particular IL-1αand IL-1 encoding gene polymorphisms in the etiopathogenesis of RAS and Behçet’s syndrome. A significantly increased frequency of IL-1- 889C allele was found in both examined groups when compared to healthy controls. Moreover, the IL-1+3962T and IL-1-511T alleles were detected more often in RAS patients than in the other study groups [38].

Different results were demonstrated by Bazrafshani et al., who in contrast to Akman et al., did not observe the increased frequency of IL-1-889C in RAS patients when compared to the control group. Meanwhile, they demonstrated a statistically significant increment in IL-1-511T and IL-6-174G frequencies in diseased subjects. Based on the obtained results the authors claimed that interleukin 1, and not interleukin 1 was a cytokine which played a crucial role in the RAS etiopathogenesis. Although both cytokines manifest similar biologic activity, an unequal receptor distribution and affinity in the oral mucosa may be a very important issue in this process [42]. In another study Bazrafshani et al. did not reveal any correlation between IL-10 (–592 and –1082) and IL-12 (1188) polymorphisms and the increased risk of RAS development [43]. Possibly, the decreased basal IL-10 concentration in people with recurrent aphthae, described by Bun~o et al. and cited above, is caused by the other, not yet determined polymorphism of IL-10 gene cluster [35].

Borra et al. found the increased expression of the Th1 gene cluster in comparison to the Th2 cluster in patients with RAS, which may confirm the thesis that the Th1-mediated immune response is the key mechanism related with the development of the disease. The increased activity of Th1-type immune response was also described in other autoimmune-mediated diseases, including Crohn’s disease, celiac disease and PFAPA (periodic fever, aphthous stomatitis, pharyngitis, cervical lympha­deno­pathy) syndrome [44].

The serotoninergic system participates in the development of some psycho-somatic conditions and disorders, including stress and depression. Taking into consideration the suggested influence of some psychogenic factors on the course and severity of the recurrent aphthous stomatitis, Victoria et al. decided to determine whether the polymorphism in the 5-HTTLPR gene promoter region, observed in subjects with depression, was also more frequent in RAS patients than in healthy controls. In RAS patients, an increased frequency of S allele was found, which corresponds with the decreased ability of serotonin expression and uptake. Such a correlation may help to understand the increased occurrence of recurrent aphthae in people with psycho-somatic disturbances [39].

Some reports suggest also the role of endothelial nitric oxide synthase (eNOS) gene polymorphisms in the development of RAS and Behçet’s syndrome. Nitric oxide mediates various biological reactions. It participates in the conversion of GTP into cGMP – a compound required in smooth muscle relaxation and in vasodilatation, it inhibits blood platelets and monocytes adhesion [45, 46].

Oksel et al. and Karasneh et al. demonstrated an in­creased frequency of Glu298Asp eNOS gene polymorphism in Turkish patients with Behçet’s syndrome when compared to healthy controls [20, 45]. Similar results were presented also by Salvarani et al. in Italy and by Kim et al. in Korea [40, 41]. Meanwhile, Karasneh et al. did not demonstrate the correlation between the discussed eNOS gene polymorphism and aphthae occurrence in the Turkish population, which may suggest that those two diseases have unrelated genetic background [20, 47].

Apart from the analysis of particular proinflammatory cytokines encoding gene polymorphisms in the development of RAS, many researches were also focused on the evaluation of the role of some human histocompatibility antigens in the disease etiopathogenesis. The basic function of the main histocompatibility complex (MHC) is to present antigen to the T lymphocytes. In order to be recognized by T cell and to stimulate the cellular immune response, an antigen needs to be conjugated with a presenting cell, therefore the frequency of particular HLA molecule types may significantly influence the immune response severity and character also in patients with recurrent aphthae. The results of the international studies of MHC in RAS patients remain inconsistent, which may suggest the ethnic background of the condition, but also may be a consequence of unequal patients’ qualification criteria and different methodology used in various studies. Table 3 illustrates correlations between the selected HLA allele and the increased risk of RAS and Behçet’s syndrome development.

In patients with recurrent aphthous stomatitis, a higher incidence of HLA-A33, HLA-B35 and HLA-B81 [48], HLA-B12 [45, 51, 52], HLA-DR7 and HLA DR5 [53, 54] and lower incidence of HLA-B5 and HLA-DR4 [53, 54] was observed when compared to healthy controls. In patients with Behçet’s syndrome, HLA-B51 [44] and HLA-DRw8 [20] were detected more often than in RAS patients and in healthy controls. Moreover, HLA-B12 was found more frequently in subjects with cutaneous and arthral type of Behçet’s syndrome than in healthy people [52]. Albanidou-Farmaki et al. tried to determine the influence of the inheritance mode of some particular HLA haplotypes on familial RAS occurrence. They failed to demonstrate the correlation between the individual HLA alleles and RAS in the examined subjects, although it was proved that RAS susceptibility was inherited in concordance with HLA haplotypes [55].

Summary

The results of the cited studies confirm that the genetic factors play a crucial role in the etiopathogenesis of recurrent aphthous stomatitis. Some of the detected gene polymorphisms (proinflammatory cytokine encoding genes) explain the increased susceptibility to develop enhanced immune response to some antigens in their carriers, which leads to the formation of aphthous erosions and ulcers. A correlation between the serotonin transcriptase encoding gene polymorphisms and RAS also seem to be very interesting and helps to understand the role of stress and psychogenic stimuli as the trigger factors in recurrent aphthous stomatitis. Variations in the endothelial nitric oxide synthase gene expression was found in studies on subjects with circulatory system diseases, e.g. with hypertension, stroke and heart infarction. Polymorphisms in eNOS gene detected in some studies in patients with Behҫet’s syndrome may indicate that the endothelial disorders and thromboembolic complications also play a role in the etiopathogenesis of this disease, although so far in none of the studies the correlation between the eNOS gene polymorphism and recurrent aphthous stomatitis was found. More profound research on a large sample of RAS patients is definitely required also in this area.

Recurrent aphthous stomatitis remains a challenge for the clinicians of various specialties. Due to unclear etiopathogenesis of the disease, the treatment is mainly symptomatic, not very effective and does not prevent the recurrences. Defining the RAS etiologic factors also in genetic studies may in future help to determine the risk of the disease onset and to develop the effective treatment. Inconsistent international genetic studies’ results and the lack of that type of studies in the Polish population suggest the necessity of such an analysis in Poland.

References

 1. Natah SS, Konttinen YT, Enattah NS, et al. Recurrent aphthous ulcers today: a review of growing knowledge. Int J Oral Maxillofac Surg 2004; 33: 221-34.

 2. Scully C, Gorsky M, Lozada-Nur F. The diagnosis and management of recurrent aphthous stomatitis: a consensus approach. J Am Dent Assoc 2003; 134: 200-7.

 3. Sook-Bin W, Sonis ST. Recurrent aphthous ulcers: a review of diagnosis and treatment. J Am Dent Assoc 1996; 127: 1202-13.

 4. McCullough MJ, Abdel-Hafeth S, Scully C. Recurrent aphthous stomatitis revisited: clinical features, associations, and new association with infant feeding practices? J Oral Pathol Med 2007; 36: 615-20.

 5. von Mikulicz J, Kümmel W. Die Krankheiten des Mundes.

3 ed. Gustav Fischer, Jena 1912.

 6. Kuczkowski J, Stankiewicz C, Kopacz A, et al. Jan Mikulicz-Radecki (1850-1905): pioneer of ednoscopy and burgery of the sinuses, throat and digestive tract. World J Surg 2004; 28: 1063-7.

 7. Scully C, Porter S. Oral mucosal disease: recurrent aphthous stomatitis. Br J Oral Maxillofac Surg 2008; 46: 198-206.

 8. Rogers III RS. Recurrent aphthous stomatitis: clinical characteristics and associated systemic disorders. Seminars in Cutaneous Medicine and Surgery 1997; 16: 278-83.

 9. Field EA, Allan RB. Oral ulceration: aetiopathogenesis, clinical diagnosis and management in the gastrointestinal clinic. Aliment Pharmacol Ther 2003; 18: 949-62.

10. Jenerowicz D, Silny W, Dańczak-Pazdrowska A, et al. Environmental factors and allergic diseases. Ann Agric Environ Med 2012; 19: 475-81.

11. Baelum J, Larsen P, Doekes G, Sigsgaard T. Health effects of selected microbiological control agents. A 3-year follow-up study. Ann Agric Environ Med 2012; 19: 631-6.

12. Akman A, Sallakci N, Coskun M, et al. TNF-αlpha gene 1031 T/C polymorphism in Turkish patients with Behçet’s disease. Br J Dermatol 2006; 155: 350-6.

13. Natah SS, Häyrinen-Immonen R, Hietanen J, et al. Immunolocalizoation of tumor necrosis factor-alpha expressing cells in recurrent aphthous ulcer lesions (RAU). J Oral Pathol Med 2000; 29: 19-25.

14. Chattopadhyay A, Chatterjee S. Risk indicators for recurrent aphthous ulcers among adults in the US. Community Dent Oral Epidemiol 2007; 35: 152-9.

15. Lewkowicz N, Banasik M, Tchórzewski H, et al. Predominance of production of Th1 type cytokines in recurrent aphthous ulceration. Dent Med Probl 2004; 42: 655-60.

16. Wardhana, Datau EA. Recurrent aphthous stomatitis caused by food allergy. Acta Med Indones-Indones J Intern Med 2010; 42: 236-40.

17. Shashy RG, Ridley MB. Aphthous ulcers: a difficult clinical entity. Am J Otolaryngol 2000; 21: 389-93.

18. Sun A, Rhong-Phong H, Chien-Ts C, et al. Some specific human leukocyte antigen (HLA)-DR/DQ haplotypes are more important than individual HLA-DR and –DQ phenotypes for the development of mucocutaneous type of Behçet’s disease and for disease shift from recurrent aphthous stomatitis to mucocutaneous type of Behçet’s disease. J Oral Pathol Med 2001; 30: 402-7.

19. Yilmaz S, Cimen KA. Familial Behçet’s disease. Rheumatol Int 2010; 30: 1107-9.

20. Karasneh JA, Hajeer AH, Silman A, et al. Polymorphisms in endothelial nitric oxide synthase gene are associated with Behçet’s disease. Rheumatology 2005; 44: 614-7.

21. Rivera-Hidalgo F, Shulman JD, Beach MM. The association of tobacco and other factors with recurrent aphthous stomatitis in an US adult population. Oral Dis 2004; 10: 335-45.

22. Chattopadhyay A, Chatterjee S. Risk indicators for recurrent aphthous ulcers among adults in the US. Community Dent Oral Epidemiol 2007; 35: 152-9.

23. Mumcu G, Cimilli H, Sur H, et al. Prevalence and distribution of oral lesions: a cross-sectional study in Turkey. Oral Dis 2005; 11: 81-7.

24. Reichart PA. Oral mucosal lesions in a representative cross-sectional study of aging Germans. Community Dent Oral Epidemiol 2000; 28: 390-8.

25. Górska R. An epidemiological study of oral recurrent aphthous stomatitis (RAS) in children, adolescents and adults, aged 13-24, in Warsaw. Przeg Epid 1997; 51: 339-47.

26. Szponar E, Ślebioda Z, Mania-Końsko A. Recurrent aphthous stomatitis in patients attending the Department of Oral Mucosa Diseases of Poznań Medical University on the basis of 10 years observation. Czas Stomatol 2006; 61: 488-94.

27. Aydemir S, Solak Tekin N, Aktunç E, et al. Celiac disease in patients having recurrent aphthous stomatitis. Turk J Gastroenterol 2004; 15: 192-5.

28. Miziara ID, Filho BCA, Weber R. AIDS and recurrent aphthous stomatitis. Rev Bras Otorrinolaringol 2005; 71: 517-20.

29. Miller MF, Garfunkel AA, Ram C, Ship II. Inheritance patterns in recurrent aphthous ulcers: twin and pedigree data. Oral Surg 1977; 43: 887-91.

30. Ship II. Inheritance of aphthous ulcers of the mouth. J Dent Res 1965; 5: 837-44.

31. Safadi RA. Prevalence of recurrent aphthous ulceration in Jordanian dental patients. BMC Oral Health 2009; 9: 31-6.

32. Kobayashi T, Sudo Y, Okamura S, et al. Monozygotic twins concordant for intestinal Behçet's disease. J Gastroenterol 2005; 40: 421-5.

33. Woźniak-Stolarska B, Sajewicz Z, Błachut K. Serum concentration of interleukin-10 in inflammatory bowel disease. Adv Clin Exp Med 2003; 12: 717-21.

34. Hall MA, McGlinn E, Coakley G, et al. Genetic polymorphism of IL-12 p40 gene in immune-mediated disease. Genes Immun 2000; 1: 219-24.

35. Bun~o IJ, Huff C, Weston WL, et al. Elevated levels of interferon gamma, tumor necrosis factor alpha, interleukins 2, 4, and 5, but not interleukin 10, are present in recurrent aphthous stomatitis. Arch Dermatol 1998; 134: 827-31.

36. Guimarães AL, Correia-Silva Jde F, Sá AR, et al. Investigation of functional gene polymorphisms IL-1beta, IL-6, IL-10 and TNF-αlpha in individuals with recurrent aphthous stomatitis. Arch Oral Biol 2007; 52: 268-72.

37. Guimarães AL, Sá AR, Victória JM, et al. Association of IL-1beta polymorphism with recurrent aphthous stomatitis in Brazilian individuals. Oral Dis 2006; 12: 580-3.

38. Akman A, Ekinci NC, Karcaroglu H, et al. Relationship between periodontal findings and specific polymorphisms of interleukin-1alpha and -1beta in Turkish patients with Behçet’s disease. Arch Dermatol Res 2008; 300: 19-26.

39. Victoria JMN, Correia-Silva J, Pimenta FJ, et al. Serotonin transporter gene polymorphism (5-HTTLPR) in patients with recurrent aphthous stomatitis. J Oral Pathol Med 2005; 34:

494-7.

40. Salvarani C, Boiardi L, Casali B. Endothelial nitric oxide synthase gene polymorphisms in Behçet's disease. J Rheumatol 2002; 29: 535-40.

41. Kim JU, Chang HK, Lee SS, et al. Endothelial nitric oxide synthase gene polymorphisms in patients with Behçet's disease and rheumatic diseases with vasculitis. Ann Rheum Dis 2003; 62: 1083-7.

42. Bazrafshani MR, Hajeer AH, Ollier WER, Thornhill MH. IL-1B and IL-6 gene polymorphisms encode significant risk for the development of recurrent aphthous stomatitis (RAS). Genes Immun 2002; 3: 302-5.

43. Bazrafshani MR, Hajeer AH, Ollier WER, Thornhill MH. Polymorphisms in the IL-10 and IL-12 gene cluster and risk of developing recurrent aphthous stomatitis. Oral Diseases 2003; 9: 287-91.

44. Borra RC, Andrade PM, Silva IDCG, et al. The Th1/Th2 im­mune-type response of the recurrent aphthous ulceration analyzed by cDNA microarray. J Oral Pathol Med 2004; 33: 140-6.

45. Oksel F, Keser G, Ozmen M, et al. Endothelial nitric oxide synthase gene Glu298Asp polymorphism is associated with Behçet’s disease. Clin Exp Rheumatol 2006; 24: S79-82.

46. Wang XL, Wang J. Endothelial nitric oxide synthase gene sequence variations and vascular disease. Mol Gen Metab 2000; 70: 241-51.

47. Karasneh JA, Baszrafshani R, Thornhill M, Ollier WER. Endo­thelial nitric oxide synthase gene polymorphisms are not associated with recurrent aphthous stomatitis. Arch Oral Biol 2009; 54: 583-7.

48. Wilhelmsen NSW, Weber R, Monteiro F, et al. Correlation between histocompatibility antigens and recurrent aphthous stomatitis in the Brazilian population. Braz J Otorhinolaryngol 2009; 75: 426-31.

49. Özdemir M, Acar H, Deniz F, et al. HLA-B*51 in patients with recurrent aphthous stomatitis. Acta Derm Venereol 2009; 89: 202-3.

50. Challacombe SJ, Batchelor JR, Kennedy LA, Lehner T. HLA antigens in recurrent oral ulceration. Arch Dermatol 1977; 113: 1717-9.

51. Malmström M, Salo OP, Fyhrquist F. Immunogenetic markers and immune response in patients with recurrent oral ulceration. Int J Oral Surg 1983; 12: 23-30.

52. Lehner T, Welsh KI, Batchelor JR. The relationship of HLA-B and DR phenotypes to Behçet’s syndrome, recurrent oral ulceration and the class of immune complexes. Immunology 1982; 47: 581-7.

53. Gallina G, Cumbo V, Messina P, Caruso C. HLA-A, B, C, DR, MT and MB antigens in recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol 1985; 59: 364-70.

54. Albanidou-Farmaki E, Kayavis IG, Polymenidis Z, Papanayotou P. HLA-A, B, C, and DR antigens in recurrent oral ulcers. Ann Dent 1988; 47: 5-8.

55. Albanidou-Farmaki E, Deligiannidis A, Markopoulos AK, et al. HLA haplotypes in recurrent aphthous stomatitis: a mode of inheritance? Int J Immunogenetics 2008; 35: 427-32.