Essentials of recurrent aphthous stomatitis (Review)

  • Authors:
    • César Rivera
  • View Affiliations

  • Published online on: June 11, 2019     https://doi.org/10.3892/br.2019.1221
  • Pages: 47-50
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Recurrent aphthous stomatitis (RAS), also known as canker sores, is the most common disease of the oral mucosa. Unlike caries and periodontal disease, patients with RAS are unable to prevent it. The clinical picture of RAS is characterized by recurrent episodes of solitary or multiple painful ulcerations without association with systemic diseases. The objective of this review is to present the essential characteristics of RAS, including its definition, pathogenesis, clinical and microscopic characteristics, proposed experimental models and recommended pharmacological management. This understanding can serve as a theoretical framework for research proposals.

1. Introduction

Recurrent aphthous stomatitis (RAS), also known as canker sores, is the most common disease of the oral mucosa (1). This review presents key aspects of RAS, integrating clinical, histological and molecular concepts that are important for every medical professional that encounters this disease to understand.

The clinical picture of RAS is characterized by recurrent episodes of solitary or multiple painful ulcerations (2) without an association with systemic diseases (3). The latter is relevant to ensure that RAS is not confused with aphthous ulcerations.

2. Differential diagnosis and epidemiology

Aphthous ulcerations (or RAS-like ulcerations) have an underlying systemic cause; therefore, they should be considered as a distinct medical condition (3). The differential diagnoses should be established with autoinflammatory syndromes, including periodic fever with adenitis, pharyngitis and aphthae (PFAPA) syndrome, Behçet's syndrome and Crohn's disease; and immunodeficiency states, including nutritional defects (such as celiac disease and other gastrointestinal disorders), immune defects (such as human immunodeficiency virus infection/acquired immune deficiency syndrome) and neutrophil defects (such as cyclic neutropenia) (4). The term RAS should be used for ulceration present in the absence of systemic disease.

The prevalence of RAS varies between 0.9 and 78% in different groups examined. In the US, for the period of 1988-1994 the prevalence was 0.89% in adults (5) and 1.64% in children (6). In Iran (2005), Jordan (2008), India (2010-2012) and China (2013-2017) reported prevalence was 25.2% (7), 70% (8), 21.7% (9) and 27.17% (10), respectively. Its onset appears to peak between 10 and 19 years of age (11) and its frequency decreases with advancing age (12).

3. Pathogenesis

The etiology and pathogenesis of RAS remain unclear. Multiple factors are associated with the establishment of this disease, including a positive family history, food hypersensitivity, smoking cessation, psychological stress and immune disturbance (11,13). However, for this evidence, there is often an absence of statistical risk analysis. Immune dysregulation linked to several triggers may facilitate the development of RAS. The roles of the immune system and inflammatory processes have been confirmed in recent large-scale bioinformatics analyses (14,15). It is known that a Th1-type hyperimmune response favors the appearance of inflammatory reactions that precede ulcerations (Fig. 1) (16,17). In addition, genetic risk factors can determine individual susceptibility to RAS; in particular, several DNA polymorphisms of the NOD-like receptor 3(18), toll-like receptor 4(19), interleukin (IL)-6(20), E-selectin (21), IL-1β and TNF-α genes (22). However, despite the large number of factors examined, the underlying cause triggering the episodes of ulcers remains to be elucidated. Therefore, clinically, the emergence of new lesions cannot be avoided at present.

4. Clinical characteristics

RAS is known to be particularly painful (15). These idiopathic ulcerations are oval lesions of different sizes with clean edges surrounded by an erythematous halo. At the center of the ulceration, the necrotic fundus is covered with a yellow-white fibrinous exudate (23). The ulcers typically present in the non-masticatory mucosa of the cheeks, lips, ventral and lateral surfaces of the tongue, non-attached gingiva, and occasionally, the soft palate (24). RAS lesions are self-limiting (simple aphthosis), resolving within 1-2 weeks in the majority of patients (25). In those affected by the disease, the ulcers can compromise important daily functions, including nutrition, speech and oral hygiene (26), and affect quality of life (27). This is important, considering that the lesions can last >2 weeks, with recurrent episodes in a period of 1-4 months (11). RAS occurs in three morphological presentations: Minor-type (Mikulicz ulcers, 2-10 mm in diameter), which is the most common (Fig. 2); major aphthous, also termed Sutton ulcers or periadenitis necrotic mucosa (>10 mm in diameter); and herpetiform ulceration, which consists of multiple small ulcers (28). Some patients have continuous oral ulcerations; in these cases, some ulcers heal as others develop, with occasional genital ulcers. This corresponds to a clinical state known as complex aphthosis (11). Complex aphthosis has an underlying systemic cause, which does not correspond with the RAS diagnosis.

5. Disease phases

The disease sequence comprises the following stages: Premonition (24 h), comprising symptoms but no visible signs of disease; pre-ulcerative (between 18 h and 3 days), comprising erythema and mild edema; ulcerative (1-16 days), comprising active ulceration; healing (4-35 days, usually #x003C;21 days), involving a decrease in symptoms and progressive healing; and remission, in which there is no evidence of ulcers (29). The ulcerative and remission phases are those that can be evaluated with greater objectivity on dental examination. Disease recurrence is established with the appearance of new ulcers. Disease severity can be determined based on the number, size and location of the lesions, pain, duration, ulcer-free periods (30) and the impact on patient quality of life (27,31).

6. Microscopic characteristics

The diagnosis of RAS is eminently clinical and is based on careful examination. The incisional or excisional biopsy of ulcers is recommended only in cases of uncertainty, when the presence of an oral disease producing ulcers or a malignancy is suspected (32). The microscopic characteristics of RAS are nonspecific. The pre-ulcerative lesion shows subepithelial inflammatory mononuclear cells with abundant mast cells, edema of the connective tissues and neutrophils lining the margins. Damage to the epithelium usually begins in the basal layer and progresses through the superficial layers, ultimately leading to ulceration and surface exudation (2,11).

7. Experimental models

At present, the only way to examine this disease has been in those patients who suffer from it. In the English literature, two models for the experimental evaluation of RAS have been proposed, both using rabbits. One of the models induces ulcers with 50% acetic acid (33,34) and the other by surgical incision in the oral mucosa (35). Neither registered methods are involved in the inflammatory processes described in RAS. As RAS is an immunologically-mediated disease, the chemical and mechanical induction of ulcers cannot be considered valid models.

8. Treatment

Therapeutic alternatives focus on reducing painful symptoms (36). Clinically, dental surgeons at present can advise patients that the ulcers are likely to heal in 2 weeks, and in more complex cases, treatment based on topical corticosteroids can be implemented (37), which is the same approach used for several diseases of unknown cause, including pemphigus, pemphigoid and oral lichen planus. Despite the use of topical corticosteroids over several years for RAS, there is a lack of high-quality evidence for their efficacy (38) and even less for systemic interventions (31). However, the recommended protocol is a combination of a topical corticosteroid plus a topical anesthetic and a buccal antiseptic (38). The combination includes triamcinolone (0.1% paste, up to four times daily) in addition to topical lidocaine (2% viscous solution, maximum 8 doses/day) and oropharyngeal chlorhexidine (0.12%, 15 ml as a mouthwash twice daily) as an adjuvant (4). Patients should be instructed to avoid recognized trigger foods, and acidic foods and drinks (39).

9. Conclusions

The key concepts associated with RAS are as follows: Its cause is unknown, it cannot be prevented, it is immunologically mediated, diagnosis is clinical, there are no experimental models for its investigation, and recommended treatment includes a combination of corticosteroids and topical anesthesia plus an antiseptic. Taking these key concepts into account, several questions require further biomedical research. These include determining what the molecular differences are between a healthy individual and a patient with RAS, determining which molecules are involved in the ulcerative phase of disease and the phase of disease remission, and establishing whether there are molecules that can predict the clinical course and the severity of ulcers. Answering these questions can open up novel therapeutic and preventive possibilities.

Acknowledgements

Not applicable.

Funding

Funding was provided by Fondo Nacional de Desarrollo Científico y Tecnológico (Fondecyt; grant no. 11180170).

Availability of data and materials

Not applicable.

Authors' contributions

CR conceived the review and analyzed the relevant literature. CR sourced the literature and wrote the manuscript. CR critically revised the manuscript, produced the figures and have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Edgar NR, Saleh D and Miller RA: Recurrent aphthous stomatitis: A review. J Clin Aesthet Dermatol. 10:26–36. 2017.PubMed/NCBI

2 

Preeti L, Magesh K, Rajkumar K and Karthik R: Recurrent aphthous stomatitis. J Oral Maxillofac Pathol. 15:252–256. 2011.PubMed/NCBI View Article : Google Scholar

3 

Jin LJ, Lamster IB, Greenspan JS, Pitts NB, Scully C and Warnakulasuriya S: Global burden of oral diseases: Emerging concepts, management and interplay with systemic health. Oral Dis. 22:609–619. 2016.PubMed/NCBI View Article : Google Scholar

4 

BMJ Best Practice: Aphthous ulcers 2018. https://bestpractice.bmj.com/topics/en-us/564/guidelines. Accessed April 26, 2018.

5 

Shulman JD, Beach MM and Rivera-Hidalgo F: The prevalence of oral mucosal lesions in U.S. adults: data from the Third National Health and Nutrition Examination Survey, 1988-1994. J Am Dent Assoc. 135:1279–86. 2004.PubMed/NCBI View Article : Google Scholar

6 

Shulman JD: Prevalence of oral mucosal lesions in children and youths in the USA. Int J Paediatr Dent. 15:89–97. 2005.PubMed/NCBI View Article : Google Scholar

7 

Davatchi F, Tehrani-Banihashemi A, Jamshidi AR, Chams-Davatchi C, Gholami J, Moradi M, Akhlaghi M, Foroozanfar MH, Barghamdi M, Noorolahzadeh E, et al: The prevalence of oral aphthosis in a normal population in Iran: a WHO-ILAR COPCORD study. Arch Iran Med. 11:207–209. 2008.PubMed/NCBI

8 

Safadi RA: Prevalence of recurrent aphthous ulceration in Jordanian dental patients. BMC Oral Health. 9(31)2009. View Article : Google Scholar

9 

Patil S, Reddy SN, Maheshwari S, Khandelwal S, Shruthi D and Doni B: Prevalence of recurrent aphthous ulceration in the Indian Population. J Clin Exp Dent. 6:e36–e40. 2014.PubMed/NCBI View Article : Google Scholar

10 

Wang H, He F, Xu C, Fang C and Peng J: Clinical analysis for oral mucosal disease in 21 972 cases. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 43:779–783. 2018.(In Chinese). PubMed/NCBI View Article : Google Scholar

11 

Akintoye SO and Greenberg MS: Recurrent aphthous stomatitis. Dent Clin North Am. 58:281–297. 2014.PubMed/NCBI View Article : Google Scholar

12 

Chavan M, Jain H, Diwan N, Khedkar S, Shete A and Durkar S: Recurrent aphthous stomatitis: A review. J Oral Pathol Med. 41:577–583. 2012.PubMed/NCBI View Article : Google Scholar

13 

Gallo Cde B, Mimura MA and Sugaya NN: Psychological stress and recurrent aphthous stomatitis. Clinics (Sao Paulo). 64:645–648. 2009.PubMed/NCBI View Article : Google Scholar

14 

Rivera C: Immune system and zinc are associated with recurrent aphthous stomatitis. An assessment using a network-based approach. J Oral Res. 6:245–251. 2017. View Article : Google Scholar

15 

Wu J, Chen ZP, Shang AQ, Wang WW, Chen ZN, Tao YJ, Zhou Y and Wang WX: Systemic bioinformatics analysis of recurrent aphthous stomatitis gene expression profiles. Oncotarget. 8:111064–111072. 2017.PubMed/NCBI View Article : Google Scholar

16 

Mimura MAM, Borra RC, Hirata CHW and de Oliveira Penido N: Immune response of patients with recurrent aphthous stomatitis challenged with a symbiotic. J Oral Pathol Med. 46:821–828. 2017.PubMed/NCBI View Article : Google Scholar

17 

Ślebioda Z, Krawiecka E, Szponar E and Dorocka-Bobkowska B: Evaluation of serum zinc levels in patients with recurrent aphthous stomatitis (RAS). BMC Oral Health. 17(158)2017.PubMed/NCBI View Article : Google Scholar

18 

Slezakova S, Borilova Linhartova P, Masopustova L, Bartova J, Petanova J, Kuklinek P, Fassmann A, Dusek L and Izakovicova Holla L: Association of the NOD-like receptor 3 (NLRP3) gene variability with recurrent aphthous stomatitis in the Czech population. J Oral Pathol Med. 47:434–439. 2018.PubMed/NCBI View Article : Google Scholar

19 

Karasneh J, Bani-Hani M, Alkhateeb A, Hassan A, Alzoubi F and Thornhill M: TLR2, TLR4 and CD86 gene polymorphisms in recurrent aphthous stomatitis. J Oral Pathol Med. 44:857–863. 2015.PubMed/NCBI View Article : Google Scholar

20 

Karakus N, Yigit S, Rustemoglu A, Kalkan G and Bozkurt N: Effects of interleukin (IL)-6 gene polymorphisms on recurrent aphthous stomatitis. Arch Dermatol Res. 306:173–180. 2014.PubMed/NCBI View Article : Google Scholar

21 

Alkhateeb A, Karasneh J, Abbadi H, Hassan A and Thornhill M: Association of cell adhesion molecule gene polymorphisms with recurrent aphthous stomatitis. J Oral Pathol Med. 42:741–746. 2013.PubMed/NCBI View Article : Google Scholar

22 

Guimarães AL, Correia-Silva Jde F, Sá AR, Victória JM, Diniz MG, Costa Fde O and Gomez RS: Investigation of functional gene polymorphisms IL-1beta, IL-6, IL-10 and TNF-alpha in individuals with recurrent aphthous stomatitis. Arch Oral Biol. 52:268–272. 2007.PubMed/NCBI View Article : Google Scholar

23 

Schemel-Suárez M, López-López J and Chimenos-Küstner E: Oral ulcers: Differential diagnosis and treatment. Med Clin (Barc). 145:499–503. 2015.(In Spanish). PubMed/NCBI View Article : Google Scholar

24 

Cui RZ, Bruce AJ and Rogers RS III: Recurrent aphthous stomatitis. Clin Dermatol. 34:475–481. 2016.PubMed/NCBI View Article : Google Scholar

25 

Rogers RS III: Recurrent aphthous stomatitis: Clinical characteristics and associated systemic disorders. Semin Cutan Med Surg. 16:278–283. 1997.PubMed/NCBI

26 

Lalla RV, Choquette LE, Feinn RS, Zawistowski H, Latortue MC, Kelly ET and Baccaglini L: Multivitamin therapy for recurrent aphthous stomatitis: A randomized, double-masked, placebo-controlled trial. J Am Dent Assoc. 143:370–376. 2012.PubMed/NCBI View Article : Google Scholar

27 

Rajan B, Ahmed J, Shenoy N, Denny C, Ongole R and Binnal A: Assessment of quality of life in patients with chronic oral mucosal diseases: A questionnaire-based study. Perm J. 18:e123–e127. 2014.PubMed/NCBI View Article : Google Scholar

28 

Albrektson M, Hedström L and Bergh H: Recurrent aphthous stomatitis and pain management with low-level laser therapy: A randomized controlled trial. Oral Surg Oral Med Oral Pathol Oral Radiol. 117:590–594. 2014.PubMed/NCBI View Article : Google Scholar

29 

Vucicevic Boras V and Savage NW: Recurrent aphthous ulcerative disease: Presentation and management. Aust Dent J. 52:10–15; quiz 73. 2007.PubMed/NCBI View Article : Google Scholar

30 

Tappuni AR, Kovacevic T, Shirlaw PJ and Challacombe SJ: Clinical assessment of disease severity in recurrent aphthous stomatitis. J Oral Pathol Med. 42:635–641. 2013.PubMed/NCBI View Article : Google Scholar

31 

Brocklehurst P, Tickle M, Glenny AM, Lewis MA, Pemberton MN, Taylor J, Walsh T, Riley P and Yates JM: Systemic interventions for recurrent aphthous stomatitis (mouth ulcers). Cochrane Database Syst Rev. CD005411. 2012.PubMed/NCBI View Article : Google Scholar

32 

Belenguer-Guallar I, Jiménez-Soriano Y and Claramunt-Lozano A: Treatment of recurrent aphthous stomatitis. A literature review. J Clin Exp Dent. 6:e168–e174. 2014.PubMed/NCBI View Article : Google Scholar

33 

Karavana Hizarcioğlu SY, Sezer B, Güneri P, Veral A, Boyacioğlu H, Ertan G and Epstein JB: Efficacy of topical benzydamine hydrochloride gel on oral mucosal ulcers: An in vivo animal study. Int J Oral Maxillofac Surg. 40:973–978. 2011.PubMed/NCBI View Article : Google Scholar

34 

Karavana SY, Gökçe EH, Rençber S, Özbal S, Pekçetin C, Güneri P and Ertan G: A new approach to the treatment of recurrent aphthous stomatitis with bioadhesive gels containing cyclosporine A solid lipid nanoparticles: In vivo/in vitro examinations. Int J Nanomedicine. 7:5693–5704. 2012.PubMed/NCBI View Article : Google Scholar

35 

Fernandes Teixeira FM, Figueiredo Pereira Md, Gomes Ferreira NL, Miranda GM and Andrade Aguiar JL: Spongy film of cellulosic polysaccharide as a dressing for aphthous stomatitis treatment in rabbits. Acta Cir Bras. 29:231–236. 2014.PubMed/NCBI View Article : Google Scholar

36 

Dan S, Jinwei Z, Qiang Z, Jianwei S and Weijun Z: Exploring the molecular mechanism and biomarker of recurrent aphthous stomatitis based on gene expression microarray. Clin Lab. 63:249–253. 2017.PubMed/NCBI View Article : Google Scholar

37 

Swain SK, Gupta S and Sahu MC: Recurrent aphthous ulcers-still a challenging clinical entity. Apollo Med. 14:202–206. 2017. View Article : Google Scholar

38 

Staines K and Greenwood M: Aphthous ulcers (recurrent). BMJ Clin Evid. 1303:2015.PubMed/NCBI

39 

Scully C: Clinical practice. Aphthous ulceration. N Engl J Med. 355:165–172. 2006.PubMed/NCBI View Article : Google Scholar

Related Articles

Journal Cover

August-2019
Volume 11 Issue 2

Print ISSN: 2049-9434
Online ISSN:2049-9442

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Rivera C: Essentials of recurrent aphthous stomatitis (Review). Biomed Rep 11: 47-50, 2019
APA
Rivera, C. (2019). Essentials of recurrent aphthous stomatitis (Review). Biomedical Reports, 11, 47-50. https://doi.org/10.3892/br.2019.1221
MLA
Rivera, C."Essentials of recurrent aphthous stomatitis (Review)". Biomedical Reports 11.2 (2019): 47-50.
Chicago
Rivera, C."Essentials of recurrent aphthous stomatitis (Review)". Biomedical Reports 11, no. 2 (2019): 47-50. https://doi.org/10.3892/br.2019.1221