Kilic SS. Recurrent aphthous stomatitis. Recent Advances in Pediatrics,  Jaypee Brothers Medical Publishers, New Delhi, ISBN 81-8061-297-X, pp 63-75 , 2004

 

Recurrent aphthous stomatitis (RAS) in children

 

Recurrent aphthous stomatitis (RAS) is characterized by periodic painful, single or multiple ulcers which heal spontaneously. These ulcerations, round and shallow, are surrounded by inflammation that chiefly involves the nonkeratinized mucosa1. RAS or canker sore is the most common oral mucosal disease, with an incidence of 2% to 66% 2 . The incidence of aphthae observed in Spain3  has been found to be 2.24% which is similar to the 2% recorded for the low socioeconomic group by Crivelli 4. Both percentages are slightly greater than the figure recorded in the North American pediatric population (1.1%) 5 .

The etiology of RAS is unknown, but has a strong hereditary component and appears to be related to an immune reaction against the oral mucosa. RAS must be distinguished from other diseases that cause recurring oral ulcers such as Behcet's syndrome, systemic lupus erythematosus, celiac disease, and Crohn's disease 6.

Aphthous ulcers are a common and painful problem. Benign aphthae tend to be small (less than 1 cm in diameter) and shallow. Most patient with RAS have no major associated medical condition other than their complaint of RAS. However, aphthous ulcers that occur in conjunction with symptoms of uveitis, genital ulcerations, conjunctivitis, arthritis, fever or adenopathy should prompt a search for a serious etiology. There are 3 clinical subtypes-minor, major, and herpetiform. Minor aphthous ulcers are the most common subtype, representing 80% to 90% of all recurrent aphthous ulcers. Clinically, RAS present as extremely painful, shallow ulcerations with an erythematous halo on unattached oral mucosa. The primary differential diagnosis is oral herpes simplex 7 .

This paper highlights recurrent aphthous stomatitis, a common ulcerative condition encountered in clinical practice. The etiology, clinical symptomatology, and topical/systemic therapies that are unique to this disorder are reviewed. Pediatricians, internists, otolaryngologists, oral surgeons, and dentists may all be expected to treat this illness but little formal training in oral medicine may be offered to many of these health care professionals.

Etiology and Epidemiology:

The Greek term aphthai was initially used in relation to disorders of the mouth and is credited to Hippocrates (460-370 BC). Today, recurrent aphthous ulceration, or recurrent aphthous stomatitis, is recognized as the most common oral mucosal disease known to human beings 8. Considerable research attention has been devoted to elucidating the causes of RAS; local and systemic conditions, and genetic, immunologic, and microbial factors all have been identified as potential etiopathogenic agents. The most common cause of oral ulcer in young children is trauma by mechanical, chemical, or thermal injuries to the oral tissues. It is mostly located on the peripheral borders of the tongue, lips, buccal mucosa, or palate. Burns on the anterior palate generally occur after eating hot food or drinking hot liquids. Children may develop traumatic ulcers on the soft palate while digit sucking. In most cases, ulcers heal within 2 weeks after removing  the source of trauma. Other associated factors include systemic diseases and nutritional deficiencies, food allergies (e.g.cheese and chocolate), genetic predisposition, immune disorders, psychological stress, the use of certain medications, and HIV infection. However, to date, no principal etiology has been discovered 7. Studies of these are not conclusive, but precipitating factors that have been identified include: stress, nutritional deficiencies, trauma, hormonal changes, diet, and immunologic disorders.  Other contributors that have received attention are: allergies, progesterone levels, psychologic factors, and a familial history. The peak age of onset for RAS is between 10 and 19 years. After childhood and adolescence, it may continue throughout the entire human lifespan without geographic or age-, sex-, or race-related preference. RAS may have a familial basis, more than 40% of RAS patients having a positive familiy history of oral ulceration.There is an increased likehood of a child developing RAS if both parents have ulcers. An increased frequency of HLAA2, HLAA11, HLA B12 and HLADR2  genes have been observed. Predisposing factors seen in a minority include haematinic (iron, folate or vitamin B12) deficiency, stress, food allergies and HIV infection 9.

Pathogenesis:

The certain etiology and pathogenesis remains unknown, but has a strong hereditary component and appears to be related to an immune reaction against the oral mucosa. The lesions of RAS are not caused by a single factor but occur in an environment that is permissive for development of lesions. These factors include trauma, smoking, stress, hormonal state, family history, food hypersensitivity and infectious or immunologic factors. The clinician should consider these elements of a multifactorial process leading to the development of lesions of RAS.

Immunological mechanisms

Oral mucosal ulcerative diseases involve immunopathological mechanisms that account for loss of adhesion between contiguous keratinocytes or to structures within the basal lamina. Some are antibody mediated, in which specific adhesion molecules of the desmosome, hemidesmosome, and basement membrane become antigenic targets. Recurrent apthous ulcers have some immunopathological features that involve T cell-mediated immunity. Although the antigens, haptens, or autoantigens are not usually apparent, it is suggested that RAS is a delayed-type hypersensitivity or cell-mediated response to an antigenic stimulus residing within the epithelium. This inflammatory lesion of the oral mucosa is thought to develop as a result of  an abnormal oral mucosal cytokine cascade leading to an enhanced cell-mediated immune response directed toward focal areas of the oral mucosa. Elevated levels of  IL-2, interferon gamma, and tumor necrosis factor alpha mRNAs have been detected in RAS lesions, consistent with a cell-mediated immune response. Lower IL-10 mRNA in RAS lesions and lower resting levels of IL-10 mRNA in the clinically normal mucosa from patients with RAS have been reported in literature. Failure to suppress the inflammatory reaction initiated by trauma or other external stimuli, likely involving a functional deficiency of IL- 10 in the oral mucosa, appears to be important in the pathogenesis of RAS 10 .
Additionally, Bazrafshani et al 11 studied some cytokine gene polymorphism (IL-1A, IL-1B, IL-1RN and IL-6 gene) which may be responsible RAS pathogenesis. Inheritance of the G allele of the IL-1B -511 polymorphism was found to be strongly associated with RAS , with increased numbers of G/G homozygotes.

Microbiological mechanisms

Microbiological status of patients with diseases of the buccal mucosa is essential for the course, outcome, and prognosis of the underlying diseases. Although, no substantial data exist to estabilish a microbial etiology for RAS, some studies have suggested a possible involvement of  Streptococcus or Helicobacter pylori in RAS development 12,13 . Streptococci and their associated antigen, glucosyltransferase D (GtfD), may be involved in the disease process of RAS, especially in the exacerbation stage. An immunogenetic background owing to cross-reactivity with Streptococcus sanguis, which is often isolated from the lesions or heat shock protein, may be possible. In addition, although some studies have disclosed elevated serum antibody titers to viridans streptococci amang RAS patients, others have yielded contradictory results. Helicobacter pylori has been detected in lesional tissue of oral ulcers and by PCR in up to 72% of examined RAS ulcers.

There has recently been renewed interest in the possible role of viruses in recurrent aphthous stomatitis . Herpesvirus virions are not demonstrable in RAS lesions, although RNA complimentary to herpes simplex virus has been detected in circulating mononuclear cells in some RAS patients 14 .The possible involvement of human herpesvirus 6 (HHV-6), and Ebstein-Barr virus  in RAS development has been proposed but the data are based upon a small group of patents. There is contradictory serological and molecular data on the etiological role for human cytomegalovirus (HCMV), or varicella zoster virus (VZV) in patients with RAS 15.

 

Diagnosis                                                                           

The diagnosis of RAS is clinical because there is no specific diagnostic test. The patient history, the physical examination, and the results of any indicated tests are important to the diagnostic process.  A complete and accurate patient history is a critical component of developing a working diagnosis.  Information regarding initiating factors, frequency of lesions, relieving factors, and aggravating factors provides historically important data.  A multispecialty approach is often necessary to evaluate patients with other systemic features. The presence or absence of associated features and the site of oral involvement guides most physicians accurately in the diagnosis.  Additional investigations, including blood tests, and occasionally the use of oral cultures or biopsy, are needed to make a definitive diagnosis 16 . But histopathology of RAS is not diagnostic and the diagnosis is primarily dependent upon the clinical history.

In most cases, the clinician should be able to differentiate herpetic lesions from aphthous ulcers. RAS lesions, which usually occur on the nonkeratinized oral mucosa, can cause considerable pain and may interfere with eating, speaking,and swallowing. Awareness of the initiation of the aphthous lesion is generally indicated by local discomfort at the lesion site. The degree of pain can vary from slight to severe and is frequently described as out of proportion to the size of the lesion. RAS lesions are characterized by the recurrence of one or more painful ulcers at intervals of days to months. Most of acute oral ulcers heal spontaneously without specific therapy being necessary, but an understanding of the cause of the ulcer is reassuring to the patient and guides the clinician in management to prevent recurrent episodes of oral ulceration, or chronicity of ulcers 17 .

RAS is divided into three clinically distinct groups, each of which consists of minor, major and herpetiform lesions. Minor aphthous stomatitis is the most common subtype, representing 80% to 90% of all recurrent aphthous ulcers. Ulceration usually begins in childhood or adolescence, there is a slight female sex predilection of 1:3. It is characterized by round or oval shallow ulcers usually less than 5 mm in a diameter and occur in crops of between one and five ulcers on non-keratinized mucosa

with a gray-white pseudomembrane enveloped by a thin erythematous halo. Minor aphthous stomatitis usually appears as a single lesion, although 1-5 ulcers may be present. Within 1 to 2 weeks of the initial presentation, the aphthous ulcer resolve without scar formation.

Major aphthous ulcer, which accounts for about 10% of cases of aphthous stomatitis, is characterized by larger (>1 cm) , deeper, more irregular ulcers. The lesions are crateriform, involving much tissue necrosis, often resulting in scarring. Aphthous major can last 6 weeks or more and can become secondarily infected with bacterial and fungal organisms.  Major aphthae typically are larger, last longer than aphthous minor, and may heal with scarring.  Lesions of aphthous major can become intractable in those with immunodeficiency disorders such as HIV and AIDS, resulting in weight loss due to painful deglutition.

Herpetiform lesions are the least common variety comprising about 10% of occurrences. The name is misleading since it suggests a herpetic infection. Rather it is the similar appearance of the ulcers that can mimic the appearance of primary herpetic gingivostomatitis. Additionally, although most commonly occurring on non-keratinized surfaces, herpetiform aphthae can infrequently appear on keratinized mucosa as can primary herpetic gingivostomatitis. Herpetiform lesions are small (1-2 mm), numerous, and shallow, and tend to fuse, producing large irregular ulcers which heal in 7 to 10 days without a scar. The age of onset of herpetiform aphthous is later than with the other types, with the initial episode usually presenting in the second or third decade of life 18 .

Differential Diagnosis

To facilitate the differential diagnosis of RAS , some components of assessment are needed. These include: prodromal signs and symptoms, lesion location, and appearance of the initial and mature lesion. Although the majority of cases are benign and resolve in less than two weeks, these ulcerations may be indicative of underlying systemic diseases ranging from vitamin deficiency to autoimmunity. In addition to that RAS must be distinguished from other diseases that cause recurring oral ulcers such as Behcet's syndrome, Sweet’s syndrome, agranulocytosis, periodic fever syndrome, systemic lupus erythematosus, celiac disease, various nutritional deficiency states, and Crohn's disease 19-25 . Complex aphthosis variants, such as  mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome, and Marshall's syndrome or PFAPA (periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis) syndrome are a recently described pediatric periodic disease characterized by recurrent febrile episodes and should be considered in differential diagnosis of RAS 26, 27 . The origin of this syndrome is unknown, and it can last for several years. During healthy periods, patients grow normally.

The aphthous-like oral ulcerations of patients with human immunodeficiency virus (HIV) disease represent a challenging differential diagnosis 28 . Children with self-abusive conditions, such as Lesch-Nyhan syndrome, may intentionally bite their lips or tongue. This behavior disorder can cause to develop of aphthous stomatitis.

Recurrent Herpetic Stomatitis

Recurrent aphthous stomatitis (RAS) and herpetic aphthous lesions are common oral disorders that are often mistaken for one another.  The confusion associated with developing an accurate diagnosis is somewhat understandable since these two very different lesions share some common characteristics.  Oral infections caused by herpes simplex type 1 are widespread, even among otherwise healthy people. While most of these herpetic infections are asymptomatic, young children are at risk for developing extensive oropharyngeal vesicular eruptions when first infected with the virus. The typical oral recurrence of HSV is one or a few vesicles grouped at the mucocutaneous junction. Herpetic lesions generally appear on keratinized tissues such as the vermillion borders of the lips, hard palate, attached gingivae, and alveolar ridges 29 . The initial infection with Herpes simplex virus (HSV) occurs in children after contact with an infected person. Following the initial infection, HSV migrates to the trigeminal ganglion, where it remains in a latent state until reactivation following exposure to trauma, stres, sunlight, cold, or immunosuppression. Prodromal symptoms of herpetic stomatitis  are local pain, tingling or itching and burning at the lesion site 30 . The herpetic lesion manifests as a cluster of small grey to white vesicles that rupture to form small punctate ulcers that are usually 1 mm or less in diameter. The development of vesicles (small blisters) within 1-2 days will help to validate the occurence of a recurrent herpes outbreak. These ulcers may coalesce into one larger ulcer up to 15 mm in size.  The vesicles rupture to  form ulcers, which heal without scarring within 2 weeks. The next stage is 'crusting,' which precedes the healing process.  Complete healing usually occur in 8-10 days.  In some persons a generalized stomatitis recurs consistenly 7-10 days after a recurrent herpetic lesion of the lip or elsewhere and is often accompanied by skin lesions of erythema multiforme. Although a self-limiting disease, this oral infection can cause significant mouth discomfort, fever, lymphadenopathy, and difficulty with eating and drinking. Symptoms may persist for 2 weeks. Diagnosis can be made clinically and confirmed by laboratory tests.

Regarding transmissibility, it is important to note that while the aphthous ulcer is not contagious, the herpetic lesion is transmissible to a susceptible host.  Herpes is communicable throughout the course of the outbreak, particularly during the vesicle and ulceration phases 29 . Table 1 presents a comparison between recurrent herpetic stomatitis and RAS.

Developing an accurate diagnosis for RAS and herpetic stomatitis  is critical to the treatment plan because the recommended treatment approaches are very different for herpetic lesions and aphthous ulcerations. Some young children require hospitalization for management of dehydration and pain control. Antiviral therapy with acyclovir has proven effective in the management of primary herpetic gingivostomatitis. Treating a herpetic lesion with topical steroids (as appropriate for an aphthous ulcer) can have serious sequelae.

Furthermore, HSV poses an infectious risk to both patients and oral health care providers, so it is important that dental professionals are up-to-date on appropriate therapies and precautions.

 

 

 

Table 1:  Comparison between recurrent herpetic stomatitis and recurrent aphthous stomatitis (RAS).

 

Herpetic stomatitis

RAS

Appearance of primary lesion

vesicle

ulcer

Appearance of mature lesion

shallow, small ulcers

ulcer (with erythematous halo)

Location

attached gingiva, hard palate,vermillion border

buccal mucosa, floor of mouth, vestibule,  tongue, oropharynx

Number

few to several

one to few

Lesion duration

1-3 weeks

1-2 weeks

Etiology

Viral

Unclear;  immunologically mediated

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Orofacial viral infections in the immunocompromised host.
Orofacial viral infections are common in immunocompromised patients. Herpes simplex virus (HSV) infections are the most common. Varicella-Zoster virus (VZV) infections are less common, but usually more severe. Epstein-Barr virus (EBV) may produce ulcers, lymphoproliferative syndromes or oral hairy leukoplakia (HL). Human herpes virus 6 (HHV 6) may be the etiology of recurrent aphthous stomatitis 31 . Research is ongoing to clarify the role of other viruses in the development of infections and lesions in the orofacial area.

Behcet's disease.
Behcet's disease is a multisystem inflammatory disorder of unknown origin, characterized by recurrent oral and genital ulcerations, ocular and cutaneous lesions, arthritis, central nervous system, and vascular disease. The most common clinical feature of Behcet's disease is recurrent oral ulceration. The oral ulcers are small and shallow but painful and can also be found on the lips, gums, tongue, and palate.

The prevalence of the disease is much higher in the Mediteranean Basin and in the Far East, especially in Japan, where one study estimated an incidence of 1 in 10 000  . There is no pathognomonic laboratory test, but there are clinical criteria to assist in establishing the diagnosis. The role of the HLA-Bw51 gene has been confirmed in recent years, although its contribution to the overall genetic susceptibility to Behcet's disease has been estimated to be only 19%. The production of a variety of cytokines by T cells activated with multiple antigens has been shown to play a pivotal role in the activation of neutrophils 20 . The International Study Group diagnostic criteria require that the patient have oral ulceration as well as two other criteria, including recurrent genital ulceration, eye lesions, skin lesions, or positive pathergy test, to make a diagnosis of Behcet's disease 32 .

Neutropenias

Congenial neutropenia is characterized by a marked decrease or lack of circulating neutrophils. Clinically, the child experiences severe, recurrent systemic infections. Oral ulcers, severe gingiviris, gingival recession, and early toot loss are common oral signs of congenial neutropenia. Granulocyte colony-stimulating factor remains mainstay of congenial neutropenia treatment 33 .

Cyclic neutropenia is characterized by the disapparence of neutrophils from the periphery blood circulation and bone marrow at regular intervals of approximately 3 weeks. In each neutrophenic phase, patients suffer from fever, chills, malaise, gingivitis and aphthous stomatitis 25, 33 .

 

 

Treatment

The lack of clarity regarding the etiology of aphthous ulcers has resulted in treatments that are largely empiric. These treatments include antibiotics, anti-inflammatories, immune modulators, anesthetics and alternative (herbal) remedies. The primary goals of therapy for RAS are relief of pain, reduction of ulcer duration, and restoration of normal oral function. Secondary goals include reduction in the frequency and severity of recurrences and maintenance of remission. RAS can be effectively managed with a variety of topical and systemic medications.

Topical medications, such as antimicrobial mouthwashes such as chlorhexidine gluconate, and topical corticosteroids, can achieve the primary goals but have not been shown to alter recurrence or remission rates 34,35 . Topical corticosteroids (hydrocortisone hemisuccinate, triamcinolone acetonide, flucinonide, betamethasone valerate, betamethasone-17 benzoate, flumethasone pivolate, beclomethasone dipropionate) remain mainstay of RAS treatment 36 . If the lesions are large and accessible, combining dexamethasone with a topical ointment or gel can reduce the signs and symptoms.Additionally, when the lesions are more diffuse, difficult to access (i.e., orophaynx), or in larger numbers, a steroid rinse is more helpful than a topical ointment or gel. Decadron (dexamethasone) elixir 0.5 mg/5 ml can be considered when treating these lesions. A trial of topical anesthetic (benzocaine 20%) in a protectant dental paste can be used. Amlexanox paste, a topical, antiulcer agent, has been shown to be helpful in reducing healing time, with an associated with minimal topical anesthetic effect. Topical immunomodulatory agents that have been suggested to be of some benefit in the management of RAS include azelastine, human alpha-interferon in cream, topical 5-aminosalicylic acid and prostaglandin E2 gel 9, 34, 37,38.

Additionally,  a number of other immunomodulatory modalities now are available. The empirical use of systemic zinc sulfate supplementation in the treatment of RAS is recommended 37,39.

Patients with frequent exacerbations or those with a severe form of RAS that is unresponsive to topical treatments often require systemic agents to control their disease. These include corticosteroids, colchicine, dapsone, pentoxifylline, levamisole and thalidomide. All therapies are palliative, and none result in permanent remission 37 . Specific dosages and formularies of these drugs may require modification in the young child. Most importantly, oral lesions that do not respond to therapeutic protocols should be referred to the appropriate specialist for definitive diagnosis and treatment, especially when immunosuppressive drugs are indicated.

Oral corticosteroids should be reserved for severe cases of major RAS that do not respond to topical agents. Colchicine is also a treatment used for aphthous stomatitis. Fontes et al 9,40 reported the results of an open trial of 54 patients treated with colchicine for aphthous stomatitis. Colchicine was prescribed at a dose of 1 to 1.5 mg/d for at least 3 months. They suggested that colchicine might be proposed in first intention in severe recurrent aphthous stomatitis, since it is effective, well tolerated and easy to use.

In patients with frequent RAS unresponsive to conventional therapies, systemic sulodexide which is  a low-molecular-weight heparin with immunosuppressive activity can also be prescribed. The effectiveness of systemic sulodexide is almost comparable with that of systemic prednisone in patients with frequent RAS, without significant adverse effects 41 .

Thalidomide is effective but, because of its toxicity and cost, should be used only as an alternative to oral corticosteroids. It is attracting growing interest because of its reported immunomodulatory and anti-inflammatory properties. Current evidence indicates that thalidomide reduces the activity of the inflammatory cytokine tumor necrosis factor (TNF)-alpha by accelerating the degradation of its messenger RNA. Thalidomide also inhibits angiogenesis. It has long been used successfully in aphthous stomatitis of Behcet's syndrome, the apparent shared characteristic of which is immune dysregulation. Many recent studies have evaluated thalidomide in patients with human immunodeficiency virus (HIV) infection; the drug is efficacious against oral aphthous ulcers.  Clinical and, in some patients, electrophysiologic monitoring for peripheral neuropathy is indicated with thalidomide therapy. With appropriate safeguards, thalidomide may benefit patients with a broad variety of disorders for which existing treatments are inadequate 42,43 .

The correction of any hematinicdeficiency is of limited benefid unless the cause is corrected. A herbal based vitamin tablet with a widerange of trace elements, seems to be of limited benefit44 .

 

 

 

 

 

 

 

 

 

 

 

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Summary:

Recurrent aphthous stomatitis (RAS) is an ulcerative condition that affects the oral mucosa without evidence of an underlying medical disorder. It is characterized by the appearance of round, shallow ulcerations surrounded by inflammation that chiefly involves the nonkeratinized mucosa. Many local and systemic factors have been associated with RAS. Although the ulcerations of RAS are multifactorial and of unknown cause, recognition of the role of patient and environmental factors may be helpful in developing recommendations for treatment and prevention of future ulcers.

 In the majority of patients, symptomatic relief of RAS can be achieved with topical corticosteroids alone, with other immunomodulatory topical agents or by combination therapy. Periodic examination of oral soft tissue can help physcians to easly recognize and treat abnormalities in affecting children.