Aphthous Ulcers

The etiology of RAS is still unknown; the condition may in fact manifest from a group of disorders of quite different etiologies rather than from a single entity.[4]

Despite many studies trying to identify a causal microorganism, RAS does not appear to be infectious, contagious, or sexually transmitted. Immune mechanisms appear to be at play in persons with a genetic predisposition to oral ulceration.

A genetic basis exists for some RAS. This is shown by a positive family history in about one-third of patients with RAS; an increased frequency of human leukocyte antigen (HLA) types A2, A11, B12, and DR2; and susceptibility to RAS, which segregates in families in association with HLA haplotypes. RAS probably involves cell-mediated mechanisms, but the precise immunopathogenesis remains unclear. Phagocytic and cytotoxic T cells probably aid in destruction of oral epithelium that is directed and sustained by local cytokine release.

Patients with active RAS have an increased proportion of gamma-delta T cells compared with control subjects and patients with inactive RAS. Gamma-delta T cells may be involved in antibody-dependent cell mediated cytotoxicity (ADCC). Compared with control subjects, individuals with RAS have raised serum levels of cytokines such as interleukin (IL)–6 and IL-2R, soluble intercellular adhesion modules (ICAM), vascular cell adhesion modules (VCAM), and E-selectin; however, some of these do not correlate with disease activity.

Cross-reactivity between a streptococcal 60- to 65-kd heat shock protein (hsp) and the oral mucosa has been demonstrated, and significantly elevated levels of serum antibodies to hsp are found in patients with RAS. Lymphocytes of patients with RAS have reactivity to a peptide of Mycobacterium tuberculosis. Some cross-reactivity exists between the 65-kd hsp and the 60-kd human mitochondrial hsp. Monoclonal antibodies to part of the 65-kd hsp of M tuberculosis react with Streptococcus sanguis. RAS thus may be a T cell–mediated response to antigens of S sanguis, which cross-react with the mitochondrial hsp and induce oral mucosal damage. RAS patients have an anomalous activity of the toll-like receptor TLR2 pathway that probably influences the stimulation of an abnormal Th1 immune response. 

Predisposing factors may include any of the following:

• Stress - This underlies RAS in some cases; ulcers appear to exacerbate during school or university examination times.

• Trauma - Biting of the mucosa and wearing of dental appliances may lead to some ulcers; RAS is uncommon on keratinized mucosae.

• Endocrine factors in some women - RAS is clearly related to the progestogen level fall in the luteal phase of the menstrual cycle, and ulcers may then temporarily regress in pregnancy.

• Cessation of smoking - This may precipitate or exacerbate RAS in some cases.

• Allergies to food - Food allergies occasionally underlie RAS; the prevalence of atopy is high. Patients with aphthae may occasionally have a reaction to cow's milk and may have been weaned at an early age.

Aphthous-like ulcers may be seen in the following:

• Hematinic deficiency: Up to 20% of patients are deficient of iron, folic acid (folate), or vitamin B.

• Malabsorption in gastrointestinal disorders: About 3% of patients experience these disorders, particularly celiac disease (gluten-sensitive enteropathy) but, occasionally, Crohn disease, pernicious anemia, and dermatitis herpetiformis. HLA DRW10 and DQW1 may predispose patients with celiac disease to oral ulceration.

• Immune deficiencies: Ulcers (aphthous-like ulcers) may be seen in patients with HIV, neutropenias, and some other immune defects.

• Drugs, especially NSAIDs, alendronate, and nicorandil[5] : These may produce mouth ulcers, but the history should distinguish them from RAS.

• Sodium lauryl sulfate (SLS): This is a detergent in some oral healthcare products that may aggravate or produce oral ulceration.

A study by Gülseren et al suggested that food additives may be involved in the etiology of RAS. In the study, patch testing was used to test for reactions to 23 food additives in 24 patients with RAS and 22 controls. The study found that 21 (87.5%) of the patients with RAS demonstrated positive patch test reactions to one or more allergens, compared with 3 (13.6%) of the controls, with the additives producing the most positive reactions in the RAS patients being cochineal red (15 patients; 62.5%), azorubine (11 patients; 45.8%), and amaranth (6 patients; 25%).[6]

A study by Zhang et al indicated that impairment of the enzymatic antioxidant defense system may be key to the pathogenesis of RAS in patients with the condition who have active lesions. The investigators found significantly lower serum levels of superoxide dismutase, catalase, and glutathione peroxidase in active lesion RAS patients than in patients in the remission stage of RAS or in healthy controls. Serum levels did not significantly differ between the remission patients and controls.[7]

Frequency

United States

RAS affects 5-66% of the population. Approximately 1% of children from higher socioeconomic groups in developed countries have RAS; however, 40% of selected groups of children can have a history of RAS, with ulceration beginning before age 5 years and with the frequency of affected patients increasing with age. Multiple factors such as the specific population evaluated, diagnostic criteria, and environmental factors, affect the prevalence of RAS.[2]  

Mortality/Morbidity

Most patients with RAS are otherwise healthy. However, a study by Wiriyakijja et al of 120 patients with RAS indicated that the condition is associated with psychological distress. Using the Hospital Anxiety and Depression Scale (HADS) and the 10-item Perceived Stress Scale (PSS-10), the investigators reported the prevalence of anxiety, depression, distress, and moderate-to-high perceived stress in the cohort to be 42.5%, 18.33%, 28.33%, and 71.67%, respectively. The study found the psychological symptoms to be linked to ethnicity, alcohol consumption, disease comorbidities, clinical type of RAS, ulcer size, pain, and RAS disease activity.[8]

Race

RAS has been reported in all races

Sex

A slight female predominance exists.

Age

RAS normally first arises in childhood or adolescence, predominantly between the ages of 10 and 19 years, with the frequency decreasing in subsequent years. The chance of children with RAS-positive parents presenting with RAS is high, up to 90%, while the chance of presentation in children with RAS-negative parents is just 20%. It is interesting to note that the prevalence of presentation has been found to be five times greater in children with high socioeconomic status.[2]

Minor aphthous ulcers (MiAUs) are usually self-limiting, with the usual duration being about 10-14 days without any active treatment. Major aphthous ulcers (MjAUs) can last up to about a month. A third type of RAS, the herpetiform ulcers, are devastating, lasting from 10 days to about 100 days. Ulcers respond well to topical medications, although sometimes a systemic medication may be necessary.

Patient education regarding this condition may facilitate early treatment during prodromal phases to minimize the discomfort. Children with extensive ulcers should receive proper diet and hydration, as they may avoid food intake as well as hydration. When using palliative measures such as topical numbing medication, the patient must be cautioned against trauma to anesthetized areas while eating or sleeping. The patient should avoid precipitating factors, such as allergens, trauma, and other potential triggers.

For patient education resources, see the Oral Health Center, as well as Canker Sores.

The 3 main clinical types of recurrent aphthous stomatitis (RAS) are as follows:

• Minor aphthous ulcers (MiAUs, 80% of all RAS)
• Major aphthous ulcers (MjAUs)
• Herpetiform ulcers.

However, any significance of these distinctions is unclear (ie, they could just be 3 distinct disorders). Diagnosis is based on history and clinical features. (See the image below.)

Recurrent aphthous stomatitis with ulcers of varying sizes - large ulcers on the right buccal mucosa and a small ulcer on the anterior tongue.

Characteristics of MiAUs (ie, Mikulicz ulcers) include the following:

• They occur mainly in persons 10-40 years of age.

• They often cause minimal symptoms.

• They are small round or ovoid ulcers 2-4 mm in diameter. (MiAUs are round or ovoid in most situations.)

• They have an ulcer floor that is initially yellowish but assumes a gray hue as healing and epithelialization proceeds.

• They are surrounded by an erythematous halo and some edema.

• They are found mainly on the nonkeratinized mobile mucosa of the lips, cheeks, floor of the mouth, sulci, or ventrum of the tongue; they are uncommonly seen on the keratinized mucosa of the palate or dorsum of the tongue.

• They occur in groups of only a few ulcers (ie, 1-6) at a time.

• They heal in 7-10 days.

• They recur at intervals of 1-4 months.

• They leave little or no evidence of scarring.

Characteristics of MjAUs (ie, Sutton ulcers, periadenitis mucosa necrotica recurrens [PMNR]) include the following:

• They are larger, of longer duration, of more frequent recurrence, and often more painful than MiAUs.

• They are round or ovoid like MiAUs but are larger and associated with surrounding edema.

• They reach a large size, usually about 1 cm in diameter or even larger.

• They are found on any area of the oral mucosa, including the keratinized dorsum of the tongue or palate.

• They occur in groups of only a few ulcers (ie, 1-6) at one time.

• They heal slowly over 10-40 days.

• They recur extremely frequently.

• They may heal with scarring.

• They occasionally are found with a raised erythrocyte sedimentation rate or plasma viscosity.

Characteristics of herpetiform ulceration (HU) include the following:

• They are found in a slightly older age group than the other RAS.

• They are mainly found in females.

• They begins with vesiculation that passes rapidly into multiple, minute, pinhead-sized, discrete ulcers.

• They involve any oral site, including the keratinized mucosa, increase in size, and coalesce to leave large round ragged ulcers.

• They heal in 10 days or longer.

• They are often extremely painful.

• They recur so frequently that ulceration may be virtually continuous.

Most patients with RAS appear to be otherwise well, but a minority have etiologic/precipitating factors that can be identified by the history. These factors may include the following:

• Dentifrices containing sodium lauryl sulfate

• Trauma

• Stress

• Cessation of smoking

• Menstrual cycle association

• Food allergy

Aphthous-like ulcers may appear in the following diseases and states:

• Hematinic deficiency (eg, iron, folate, vitamin B-12)

• Celiac disease

• Crohn disease

• Behçet syndrome, which may include genital, cutaneous, ocular, or other lesions (The mouth ulcers in Behçet syndrome often mimic major aphthae, with frequent episodes and long duration to healing.)

• Immunodeficiencies such as human immunodeficiency virus (HIV) infection, and neutropenia (Ulcers appearing on a regular 3-week cycle may indicate cyclic neutropenia.)

• Auto-inflammatory syndromes, such as periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA) in children

• Malignancy (Ulcers appearing for the first time in an older individual may reflect underlying systemic disease [eg, colonic carcinoma with chronic hemorrhage].)

• Drug use (eg, cytotoxic drugs, nicorandil, NSAIDs, others)

• Sweet syndrome, a rare immunologically mediated condition that belongs to the group of neutrophilic dermatoses and must be differentiated, particularly from Behçet disease

  • Sweet syndrome is characterized by red-brown plaques and nodules that are frequently painful and occur primarily on the head, neck, and upper extremities.

  • Patients often also have neutrophilia and fever and may have oral ulceration.

RAS ulcers, which can occur in otherwise healthy patients, are relatively small recurrent, round or ovoid ulcers with well-circumscribed erythematous margins presenting like a halo and with a yellow or gray floor. For 2-48 hours before an ulcer develops, RAS is characterized by a prodromal burning sensation.[2] Ulcers commonly present on lining oral mucosa, such as buccal and labial mucosa, and on the tongue, rather than on attached oral mucosa.

A report of oral ulceration on routine physical evaluation or oral ulceration presenting as the patient's chief complaint should prompt a thorough extraoral and intraoral examination. When an active ulcer is noted, a recall in 2 weeks will be beneficial to monitor the prognosis. No specific investigations exist for RAS; however, a linear ulceration in areas of the buccal or labial vestibule may warrant further workup, since the other causes of recurrent mouth ulceration should be excluded. Indeed, any ulcer that lasts for more than 3 or 4 weeks requires evaluation to rule out other, serious disease processes. If a solitary, nonhealing ulcer is reported, a biopsy may be warranted and the clinician should rule out malignancy.

Some RAS cases involve a familial and genetic basis; approximately 40% of patients with RAS have a familial history, but inheritance may be polygenic with penetrance dependent on other factors. Studies by Chen and Wu indicated that the presence of the interleukin family gene polymorphism IL-1β+3954C/T is a risk factor for RAS.[9, 10]

Most relevant studies have found hematinic (eg, iron, folic acid, vitamin B-12) deficiencies in as many as 20% of patients with recurrent ulcers. In addition, deficiencies of vitamins B-1, B-2, and B-6 have been noted in some patient cohorts.

The previously proposed association between recurrent ulcers and celiac disease (gluten-sensitive enteropathy [GSE]) is tenuous, despite some evidence that the haplotype of HLA-DRW 10 and DQW1 may predispose patients with GSE to RAS.

Hypersensitivity reactions to exogenous antigens other than gluten do not have a significant etiologic role in RAS, and associations with atopy are inconsistent. Moreover, a consistent association between aphthous ulceration and psychological illness, zinc deficiency, or sex hormone levels is unlikely.

Local physical trauma may initiate ulcers in susceptible people, and RAS is uncommon where mucosal keratinization is present or in patients who smoke tobacco.

A study by Tecco et al of children aged 5-10 years found that the presence of decayed teeth was associated with the existence of minor RAS, with an odds ratio of 3.15.[11]

Various microorganisms have been examined for a causal association. Latterly, Helicobacter pylori has been detected in lesional tissue of ill-defined oral ulcers, but the frequency of serum immunoglobin G (IgG) antibodies to H pylori is not increased in RAS. On the other hand, a study by Gülseren et al indicated that H pylori may play a role in the etiology of RAS. The rapid urease test was used to find the bacterium in dental plaque samples from 34 of 38 patients with RAS (89.5%), compared with 24 of 43 controls (55.8%).[12]

A study by Hijazi et al also suggested that the development of idiopathic RAS is associated with changes in the mucosal microbiome. The investigators found, for example, that species of the bacterial family Porphyromonadaceae related to periodontal disease were more abundant in ulcerated areas in the mucosae of patients with RAS than in the mucosae of healthy controls. In contrast, species of the bacterial family Streptococcaceae that are associated with oral health were more abundant in the healthy controls than in the ulcerated areas of RAS patients.[13]

Similarly, a study by Kim et al suggested that dysbiosis contributes to the development of RAS. In an analysis of the oral mucosa and saliva from RAS patients and controls, the investigators found that the patients with RAS had reductions in healthy core microbiota and increases in rare microbial species. These changes included decreases in Streptococcus salivarius and increases in Acinetobacter johnsonii.[14]

Another study, by Stehlikova et al, indicated that Mogibacterium timidum may play a part in the pathogenesis of RAS, with the investigators having found higher serum levels of IgG antibodies against the bacterium in patients with RAS than in controls.[15]

Little evidence suggests an etiologic association between viruses and RAS. Human herpesvirus (HHV)–6 and HHV-7 DNA has not been demonstrated in RAS, but HHV-8 DNA is present in HIV-related oral ulcers.

It is important to rule out any underlying cause in the case of oral ulcers. A thorough history is essential, since this and a review of systems can assist the clinician in determining whether ulcers are related to a systemic inflammatory process or are truly idiopathic. Diseases causing oral ulcers that should not be mistaken for recurrent aphthous stomatitis (RAS) include Behçet syndrome, cyclic neutropenia, recurring intraoral herpes infections, human immunodeficiency virus (HIV)–related oral ulcers, and gastrointestinal diseases such as Crohn disease and ulcerative colitis. Minor aphthous ulcers (MiAUs) most commonly form on nonkeratinized oral mucosa, usually on the buccal and labial mucosa; they have a duration of about 10-14 days without scar formation.[2]

See the list below:

• Systemic disorders should particularly be suspected in the presence of features that may suggest a systemic background.

• Diagnosis of recurrent aphthous stomatitis (RAS) is based on history and clinical features. No specific tests are available; however, to exclude systemic disorders discussed above, the following tests may be helpful:

  • Complete blood cell count

  • Hemoglobin test

  • White blood cell count with differential

  • Red blood cell indices

  • Iron studies (usually an assay of serum ferritin levels)

  • Red blood cell folate assay

  • Serum vitamin B-12 measurements

  • Serum antiendomysium antibody and transglutaminase assay (positive in celiac disease)

• Rarely, biopsy may be indicated in cases in which a different diagnosis is suspected. Occasionally, for example, pemphigus may mimic RAS. Occasional RAS can mimic a neoplasm, necrotizing sialometaplasia, or TUGSE (traumatic ulcerative granuloma with stromal eosinophilia).

The histology of RAS is nonspecific. The ulcer is depressed well below the surface, and the inflammation extends deeply. The surface of the ulcer is covered by a fibrinous exudate infiltrated by polymorphs. Beneath is a layer of granulation tissue with dilated capillaries and edema. Deeper still is a repair reaction, with fibroblasts in the surrounding connective tissue laying down fibrous tissue. 

Identify and correct predisposing factors for recurrent aphthous stomatitis (RAS). Ensure that patients brush atraumatically (eg, with a small-headed, soft toothbrush) and avoid eating particularly hard or sharp foods (eg, toast, potato crisps) and avoid other trauma to the oral mucosa.

SLS should be avoided if implicated as a predisposing factor. Any iron or vitamin deficiency should be corrected once the cause of that deficiency has been established. If an obvious relationship to certain foods is established, these should be excluded from the diet. Patch testing may be indicated to reveal allergies. The occasional patient who relates ulcers to her menstrual cycle or to use of an oral contraceptive may benefit from suppression of ovulation with a progestogen or a change in the oral contraceptive.

In most cases, the natural history of RAS is one of eventual remission. However, for some patients, remission occurs spontaneously several years later; thus, treatment is indicated in these patients if discomfort is significant. Relief of pain and reduction of ulcer duration are the main goals of therapy. There is a huge range of supposed or possible remedies available, but objective evidence shows the most efficacy from corticosteroids and antimicrobials used topically.[16, 17]

Topical corticosteroids (TCs) remain the mainstays of treatment. A spectrum of different TCs can be used. At best, TCs reduce painful symptoms but not the rate of ulcer recurrence. The commonly used preparations are as follows:

• Hydrocortisone hemisuccinate pellets (Corlan), 2.5 mg used 4 times daily

• Triamcinolone acetonide in carboxymethyl cellulose paste (Adcortyl in Orabase [withdrawn in some countries], Kenalog), administered 4 times daily

• Betamethasone sodium phosphate as a 0.5-mg tablet dissolved in 15 mL of water to make a mouth rinse, used 4 times daily for 4 minutes each time

Hydrocortisone and triamcinolone preparations are popular because neither causes significant adrenal suppression; however, ulcers still recur.

Betamethasone, fluocinonide, fluocinolone, fluticasone, and clobetasol are more potent and effective than hydrocortisone and triamcinolone, but they carry the possibility of some adrenocortical suppression and a predisposition to candidiasis.

Other topical medications that can reduce discomfort include the nonsteroidal anti-inflammatory drugs (NSAIDs) diclofenac and amlexanox paste; the latter has been found to shorten the time it takes minor aphthae to heal. Swishing three or four times daily with so-called “magic mouthwash” (MMW) can also offer some pain relief.[2] MMW can be obtained in several formulations, an example being as follows:

• One part viscous lidocaine 2%
• One part Maalox (do not substitute Kaopectate)
• One part diphenhydramine (12.5 mg per 5 mL)

Benzydamine hydrochloride mouthwash, though no more beneficial than a placebo, can produce transient pain relief. Chlorhexidine gluconate and bioadhesive (Gelclair) mouth rinses reduce the severity and pain of ulceration but not the frequency.

Topical tetracyclines may reduce the severity of ulceration, but they do not alter the recurrence rate. A doxycycline capsule of 100 mg in 10 mL of water administered as a mouth rinse for 3 minutes or tetracycline 500 mg plus nicotinamide 500 mg administered 4 times daily may provide relief and reduce ulcer duration. Avoid tetracyclines in children younger than 12 years who might ingest them and develop tooth staining.

If RAS fails to respond to local measures, systemic immunomodulators may be required. A wide spectrum of agents has been suggested as beneficial, but few studies have been performed to assess the efficacy of these drugs (or their adverse effects are significant). Thalidomide 50-100 mg daily is effective against severe RAS, although ulcers tend to recur within 3 weeks. Teratogenicity, neuropathy, and other adverse effects dissuade most physicians from its use.

Oral vitamin B-12 may significantly reduce or eliminate RAS recurrences. For example, a randomized, double-blind, placebo-controlled study by Volkov et al found that in patients taking 1000 μg of sublingual vitamin B-12 daily for 6 months, there was a significant decrease in the number of ulcers and level of pain, as well as in the duration of outbreaks, at 5 and 6 months no matter what the patients' initial B-12 blood levels had been. Moreover, during the sixth month of treatment, 74.1% of the patients taking B-12 achieved "no aphthous ulcers status," compared with 32.0% of patients in the control group.[18]

Few, if any, of the other medications used for RAS have undergone serious scientific evaluation. These include aloe vera, biologics, transfer factor, gamma-globulin therapy, sodium cromoglycate lozenges, dapsone, colchicine, pentoxifylline, levamisole, colchicine, azathioprine, prednisolone, azelastine, alpha 2-interferon, ciclosporin, deglycerinated liquorice, 5-aminosalicylic acid (5-ASA), prostaglandin E2 (PGE2), sucralfate, diclofenac, and aspirin.

A randomized, single-blind, placebo-controlled trial by Albrektson et al indicated that low-level laser therapy can relieve RAS pain. The study, which involved 40 patients with RAS, also found that patients who received laser treatment found it easier to eat, drink, and brush their teeth than did the placebo patients.[19]

Similarly, a literature review by Khaleel Ahmed et al suggested that low-level laser therapy is superior to topical medications in reducing pain and lesion size in patients with RAS. Moreover, in one of the reports included in the review, diode laser treatment at 635 nm was found to reduce pain more quickly than did therapy at 450 or 808 nm.[20, 21]

Patients with oral ulcers typically present to a general dentist. These dentists are usually well versed in primary management of such lesions, but if the presentation is severe or the ulcers are recalcitrant to topical therapy, a systematic workup and management beyond topical therapies may be essential, as the condition may compromise diet and hydration and significantly impact the patient's quality of life. These cases may be beyond the scope of a general dentist, and referral to a specialist in oral medicine may be necessary. Depending on the etiology of the ulcers, interdisciplinary care may be needed with, as applicable, a gastroenterologist, an immunologist/allergologist, a hematologist, a rheumatologist, and a dermatologist.

The patient should avoid consuming any foods that could lead to RAS.

TCs remain the mainstay of treatment for recurrent aphthous stomatitis (RAS). TCs reduce the number of ulcer days compared with controls, but they have no consistent effect on the frequency of ulceration. TCs may reduce the ulcer duration and pain. Amlexanox oral adhesive pellicles or oral adhesive tablets appear to reduce ulcer pain and duration.

Chlorhexidine gluconate mouth rinses reduce the severity and pain of ulceration but do not affect the frequency.

The range of systemic medications available is of variable or unproven efficacy or may have serious adverse effects; such agents include systemic corticosteroids, colchicine, clofazimine, and thalidomide (and many others).[22]

Class Summary

A spectrum of different TCs can be used. All can reduce symptoms, and neither hydrocortisone nor triamcinolone preparations cause adrenal suppression. Ulcers still recur.

Hydrocortisone topical (Cortaid, Dermacort, Westcort)

Decreases inflammation by suppressing migration of PMNs and reversing increased capillary permeability.

Triamcinolone topical (Aristocort, Flutex, Kenalog)

Decreases inflammation by suppressing migration of PMNs and reversing capillary permeability.

Betamethasone topical (Alphatrex, Diprolene, Maxivate)

For inflammatory dermatoses responsive to steroids. Decreases inflammation by suppressing migration of PMNs and reversing capillary permeability.

Fluocinolone (Synalar, Fluonid)

High-potency topical corticosteroid that inhibits cell proliferation and is immunosuppressive, antiproliferative, and anti-inflammatory.

Fluocinonide (Fluonex, Lidex)

High-potency topical corticosteroid that inhibits cell proliferation and is immunosuppressive and anti-inflammatory.

Clobetasol (Temovate)

Class I superpotent topical steroid; suppresses mitosis and increases synthesis of proteins that decrease inflammation and cause vasoconstriction.

Class Summary

Mucoadhesive action reduces pain by adhering to the mucosal surface of the mouth.

Bioadherent oral (Gelclair)

This agent adheres to the mucosal surface of mouth and forms a protective coating that shields exposed and overstimulated nerve endings. Ingredients include water, maltodextrin, propylene glycol, polyvinylpyrrolidone (PVP), sodium hyaluronate, potassium sorbate, sodium benzoate, hydroxy ethylcellulose, polyethylene glycol (PEG)–40, hydrogenated castor oil, disodium edetate, benzalkonium chloride, flavoring, saccharin sodium, and glycyrrhetinic acid.

Avoid precipitants (eg, trauma).

Scarring can be severe in rare cases.

The natural history of RAS is of amelioration with age.