Recurrent Aphthous Stomatitis: An Enigmatic Entity and Sign of Systemic Disease

Abstract

Recurrent aphthous stomatitis (RAS) is a common oral disease characterized by intermittent eruptions of painful oral ulcerations. Hippocrates first described aphthous stomatitis with the Greek word aphthi meaning “to inflame.” RAS affects 10–20% of the population with the incidence being the highest among young adults. The peak age of onset is between 10 and 19 years of age. It has three main forms of presentation. The most common being minor RAS, along with the major and herpetiform types. Many local and systemic factors are associated with RAS pathogenesis. The main concern with oral aphthae in many cases is local pain, which can be severe enough to interfere with eating, speaking, and swallowing. It is important to differentiate RAS from systemic diseases with aphthae—such as Behçet's syndrome and the newly-delineated, autoinflammatory PFAPA (periodic fever with aphthous stomatitis, pharyngitis, and adenitis) syndrome—as well as from other aphthous-like ulcerations like herpes simplex virus (HSV) or Coxsackie oral lesions. The management depends upon the clinical presentation and symptomatology—focusing on analgesic, antimicrobial, and immunomodulatory drugs.

Introduction

Aphthous ulcers are small, shallow, non-contagious sores affecting oral mucous membranes, save for gingiva and hard palate. They are common, recurrent, and annoying. These aphthae must be distinguished from vesicular eruptions, which may create ‘aphthous-like’ ulcers following rupture. A recent study on patients with benign oral mucosal lesions reported that 13.7% suffered from RAS.[1] Aphthous stomatitis typically occurs on the movable oral mucosa such as labial and buccal mucosa, soft palate, ventral tongue, and floor of the mouth.[2] Aphthous stomatitis may be classified based upon symptomatology. The former Aphthous stomatitis is characterized by a mild clinical course of up to four recurrences of one or more ulcers per year with each episode lasting up to 14 days. In complex aphthosis, patients experience the nearly continuous presence of numerous, large painful oral ulcers that take 4–6 weeks to heal. The affected patients often have at least one active ulcer.[3,4]

Aphthous ulcers are also classified based on size, number, and morphology into minor, major, and herpetiform subtypes [Table 1]. The minor form, also known as Mikulicz ulcer, is the most common, accounting for approximately 80% of the patients.[2,5,6,7] These tend to be small, less than 5 mm in diameter, and are usually multiple. Preceding their appearance is often a burning sensation. They have a predilection for the non-keratinized oral epithelium and usually heal within 2 weeks without scarring [Figure 1].[2,5,6,7,8] The major RAS, also known as periadenitis mucosa necrotica recurrens or Sutton's disease, affects approximately 5–10% of all RAS patients. These are more severe, causing more damage and pain than the minor form; the aphthae are deeper and generally greater than 1 cm in diameter. The major aphthae have a post-pubertal onset, are often solitary, and have a predilection for the posterior oral cavity. They may persist for weeks to months and heal with fibrotic scars. These major aphthae typically form on the lips, soft palate, and oropharynx and often cause scarring. This form of RAS may be associated with human immunodeficiency virus (HIV) infection, implicating a disturbance of immune function in their pathogenesis.[2,6,7,8,9] RAS in HIV patients must be differentiated from infectious ulcers, which may have atypical presentations.[10]

Table 1.

Clinical features of recurrent aphthous stomatitis and primary herpetic gingivostomatitis

	Minor RAS	Major RAS	Herpetiform RAS	Primary herpetic gingivostomatitis
Percentage of RAS cases	80-90%	5-10%	5-10%	-
Peak age decade of onset	2nd	1st and 2nd	3rd	-
Number	1-10	1-5	5-100	1-100
Size in cm	<1.0	>1.0	>0.3	<0.3
Location	Buccal mucosa	Labial mucosa	Predominantly non-keratinized mucosa	Perioral skin
	Labial mucosa	Soft palate	Floor of mouth	Keratinized and non-keratinized oral mucosa; gingival inflammation is a key feature
	Floor of mouth	Oropharynx	Ventral surface of the tongue but may involve keratinized tissues
	Ventral tongue
Duration in days	7-14	15-60	7-14	1-8 days
Scar formation	Rare	Common	None	None
Morphology		Gray-white pseudo membrane base	Small punctate ulcers coalesce to form irregular erosions	Vesicular eruption forming punctate ulcers or irregular erosions
		Oval-to-round lesions
		Halo of erythema
		Smooth borders
Comments		Associated with severe pain and dysphagia	Ulcers can coalesce to form large erosions. No systemic signs and symptoms	Acute onset
			Non-contagious	May be associated with sore throat, malaise, halitosis, lymphadenopathy, and fever
				Contagious

Figure 1.

Minor aphthous ulcers affecting (a) soft palatal mucosa, (b) ventral tongue, (c) labial mucosa, and (d) the floor of the mouth

Herpetiform aphthous stomatitis is the least common variant, with an onset between 20 and 30 years of age. Herpes simplex virus (HSV) does not contribute to the formation of these ulcers.[5,8,9,11,12,13,14] This form manifests as localized or diffuse crops of 10–100 ulcers each 2–3 mm in size which can coalesce to form irregular erosions [Figure 2]. Ulcers predominantly affect non-keratinized mucosa such as labial or soft palatal mucosa, and ventral tongue. The involvement of keratinized tissues such as the dorsal tongue is also possible. They resolve faster than major RAS ulcers, generally lasting 7–14 days. With their herpetiform morphology, they must be differentiated from the ulcers of primary herpetic gingivostomatitis as illustrated in Figure 3.

Figure 2.

Herpetiform aphthous ulcers involving the left ventral tongue and the floor of the mouth

Figure 3.

Primary herpetic gingivostomatitis demonstrating inflammation of maxillary gingiva and punctate ulcers resembling aphthous ulcers involving the buccal and soft palatal mucosa

Pathophysiology of RAS

The etiology of RAS is most likely multifactorial. There is some evidence of a familial component with early onset and greater severity—as suggested by twin studies, though no specific gene has been identified.[15] The possible systemic precipitating factors include stress, vitamin/mineral deficiencies (folate, iron, zinc, vitamin B), food allergies, gluten-sensitive enteropathy, and drugs (e.g., nicorandil,[16] etanercept[17]).[4,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]

Interestingly, the frequency of RAS increases in those who quit smoking, possibly due to a loss of either mucosal keratinization promoted by tobacco smoke, or the protective effect of nicotine.[37] Nicotine replacement therapy has proven efficacious in improving ulcers resulting from the cessation of tobacco products.[38] Many studies support the idea that immune dysregulation leads to an exaggerated inflammatory response and/or a relatively weak anti-inflammatory response in RAS.[18]

Although most cases of RAS are isolated, aphthous ulcers may be seen as part of or in association with many systemic disorders. For instance, Behçet's syndrome is an autoimmune vasculitis that gives rise to recurrent oral and genital ulcerations, arthritis, pustular vasculitic cutaneous lesions, uveitis, and retinitis. Its oral ulcers are often the initial symptom. They are typically painful, variable in size, and can be shallow or deep. Behçet's syndrome can typically be differentiated from RAS by the presence of systemic symptoms.[33] Another syndrome producing similar clinical manifestations is reactive arthritis syndrome, which is associated with oral ulcers, uveitis, conjunctivitis, and human leukocyte antigen (HLA)-B27-positive arthritis.[39] Another autoimmune condition which may include aphthae as part of the clinical manifestations is inflammatory bowel disease.[34,35,40] The differentiation of aphthae in this context from RAS rests on the review of systems for gastrointestinal complaints and pertinent systemic workup.

A hematologic disease that produces oral aphthae is cyclic neutropenia. These blanched oral aphthae are associated with neutropenic periods and fever. If fever and oral ulcers consistently occur simultaneously, a hematologic analysis should be considered.[36] There is also a higher occurrence of aphthae among HIV patients, particularly major aphthae. Clinicians should consider the possibility of immunosuppression, whether HIV infection or underlying leukemia/lymphoma, in those who develop aphthae that are large and slow to heal.

Aphthous ulcers are also a component of the PFAPA syndrome (periodic fever with aphthous stomatitis, pharyngitis, and adenitis). Commonly between the ages of 1 and 4 years, PFAPA is first evident with abrupt fevers for 2–7 days, pharyngitis with or without tonsillar exudates, cervical lymphadenopathy, and aphthous ulcers. Its symptoms may recur every 2–12 weeks. These non-scarring aphthae are often on the lips or buccal mucosa; they are smaller and less painful than those of the Behçet's syndrome.[41] Though normally resolving in between episodes, the ulcers may be present the day preceding cyclical fever. The PFAPA syndrome seldom lasts beyond 10 years of age.[42,43] Although a self-limiting disease, the symptomatic treatment for PFAPA involves oral steroids. Severe cases may require tonsillectomy, which has been shown to resolve most PFAPA symptoms except for the fevers.[44,45,46]

Diagnostic Workup

The diagnostic workup should start with a thorough history of the number, size, duration, and frequency of ulcers as well as the age of onset, familial incidence, and presence of mucocutaneous lesions elsewhere in the body. The patients should also be questioned about medications and over-the-counter products they use, xerostomia, environmental exposures, food sensitivity, oral hygiene practices, hematinic deficiency, psychological stress, HIV status, and symptoms of organ system involvement. When positive findings on history, physical, or review of systems raise the suspicion of systemic conditions with aphthous ulcers rather than isolated RAS, additional investigations are warranted [Table 2]. The management of these systemic conditions helps improve aphthous manifestations. Local therapy directed at ulcers also provides additional benefits.

Table 2.

Systemic conditions and syndromes associated with aphthae

Syndromes	Distinguishing characteristics	Work up
Behçet’s disease	Genital ulceration	Eye evaluation for uveitis
	Uveitis/retinitis	Pathergy test
Reactive Arthritis Syndrome	Uveitis	Clinical diagnosis
	Conjunctivitis
	HLA B27 arthritis
Inflammatory bowel disease	Gastrointestinal symptoms, Recurrent bloody or mucous diarrhea	CBC, CMP, FOBT, Colonoscopy
Cyclic neutropenia	Periodic fever	Weekly CBC for 5 consecutive weeks
	Neutropenia
Human immunodeficiency virus (particularly major RAS)	Aphthae tend to be large and slow to heal	HIV antibody testing
Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome	Pharyngitis Cervical lymphadenopathy (painful) Periodic fevers at regular intervals of 2-8 weeks	Clinical diagnosis

RAS should be distinguished from other diseases that can produce oral ulcerations [Table 2]. Most commonly, RAS needs to be differentiated from the aphthous-like HSV-induced ulcers, whether primary or recurrent. Primary herpetic gingivostomatitis (PHGS) is usually evident with fever, lymphadenopathy, sore throat, halitosis, bright gingival erythema, and a vesiculoulcerative eruption in and around the oral cavity.[2,11] It is highly contagious, posing a risk of autoinoculation and transmission to others. In general, the presence of perioral lesions, gingival inflammation, and systemic signs and symptoms as well as involvement of both movable and non-moveable oral mucosa distinguish PHGS from aphthae.

In the immunocompetent host, recurrent intraoral herpes (RIH) has a propensity to arise on the hard palate and gingival mucosa, which contrasts with the ulcers of RAS that almost exclusively form on the buccal and labial mucosa, ventral tongue, and soft palate.[37] Aphthae in RAS are typically more than 3 mm in size compared with HSV ulcers, which start as vesicles, tend to be smaller, and clustered together. These vesicles ulcerate upon rupture. In the immunocompromised host, RIH may involve both keratinized and non-keratinized mucosa rendering differentiation from RAS challenging. Aphthous ulcers have non-specific histology but laboratory studies such as Tzanck smear, biopsy, viral culture, and polymerase chain reation (PCR) for patients with active lesions—or serologic testing for those without—may be used to diagnose aphthous-like conditions such as HSV or hand-foot-mouth disease.[47,48]

Herpangina and hand-foot-and-mouth disease, caused by Coxsackie A viruses, also produce oral ulcerations. However, herpangina and hand-foot-and-mouth disease ulcers begin as vesicles and occur with fever and malaise, which is not typical for RAS. Furthermore, the hand-foot-and-mouth disease has characteristic cutaneous findings of non-pruritic macules, papules, or vesicles on the hands, feet, buttocks, arms, or legs.[49]

Other ulcerative disorders which occasionally produce aphthous-like oral ulcers include cytomegalovirus (CMV), varicella-zoster virus (VZV), syphilis, pemphigus, lichen planus, and erythema multiforme.[2,5,9,50] An atypical form of pemphigus can start with small lesions resembling RAS; however, the jagged edges of ulcers, vesicular onset, and chronicity of pemphigus can help exclude RAS. Oral ulcerations of erythema multiforme also start with vesicles,[51] which upon eruption cause irregular superficial erosions clinically distinguishable from the aphthous ulcerations.[51]

Treatment and Management

Treatment for RAS can be challenging. There are many categories of drugs that are used to treat the symptoms, which can range from bothersome to incapacitating. The primary goals of the treatment for RAS include (1) to manage the pain of the ulcer(s), (2) to promote healing and reduce duration, and (3) to restore normal oral function. An important step in the management of RAS is educating the patient about the potential role of the environmental, dietary, and traumatic triggers as well as avoidance of products which may precipitate an episode or cause irritation to the existing ulcers.

For the local disease, the mainstays of therapy are topical anti-inflammatory agents. The topical corticosteroids triamcinolone, fluocinonide gel, and clobetasol ointment with or without mucosal adhesive agents such as orabase or zilactin, decrease the duration of the ulcers and increase the time between the episodes.[52,53] Another topical treatment with anti-inflammatory effects is amlexanox, the only FDA-approved drug for RAS.[54] Amlexanox works by inhibiting leukotrienes and histamines, resulting in accelerated healing times and resolution of pain.[55] Mucosal adhering agents, used alone, provide hours of pain relief by forming an impermeable barrier, protecting the existing ulcer from further trauma. Zilactin, a hydroxypropyl cellulose film, is a mucosal adhering agent that remains on the oral mucosa longer than orabase.[7,56] A mucoadhesive buccal film of benzydamine hydrochloride may also be effective.[57] Sucralfate suspensions also serve as physical barriers that decrease the pain and duration of oral and genital lesions in Behçet's disease.[58,59]

Other topical agents used to combat RAS include antimicrobial mouthwashes. These rinses are intended to prevent microbial contamination and the resulting superinfection. The two proto-typical agents that have been employed include antibiotics (mainly tetracycline) and antiseptic agents such as chlorhexidine gluconate. Tetracycline has been reported to decrease the pain and duration of ulcers.[60] Chlorhexidine gluconate also limits the number of ulcer days, reduces secondary infections, and increases the interval between ulcer recurrences.[61] However, neither mouth rinse has been shown to prevent recurrences from happening altogether.[62] The Chinese herbal medicines may be a reasonable approach, although the current evidence is limited.[63]

For many individuals, especially those with major RAS, pain from aphthae can impair oral function to the point of causing weight loss. As a result, the patients should be encouraged to maintain normal fluid and nutritional intake, while avoiding spicy and abrasive foods. Individuals sensitive to sodium lauryl sulfate should avoid toothpastes that contain it. Topical anesthetics, such as 2% lidocaine, are applied directly to the ulcer to decrease pain.[2] A few randomized trials have also shown that laser cauterization reduces RAS pain, though it demonstrated no changes in the healing time or recurrence rate.[64,65]

For many RAS patients, topical agents are sufficient to manage symptoms and promote healing. However, the efficacy of topical medications is limited. On the other hand, the use of systemic agents should be reserved for patients with systemic diseases, with frequent episodes of copious painful aphthae, ulcerations that are resistant to topical therapy, or erosions that develop in the oropharynx or esophagus. Systemic steroids like prednisone will generally heal the pain and inflammation of most ulcers.[66,67] Similarly, biologics such as anti-tumor necrosis factor (TNF)-α agents (e.g., infliximab) have also been successful in the trials for recalcitrant/severe RAS, though steroids and biologics both carry serious side effect risks.[68,69] A low-dose oral steroid therapy for PFAPA syndrome may expeditiously halt flares.[46] The need for frequent treatment with prednisone or other systemic immunosuppressants is a sign to initiate therapy with less toxic immunomodulatory agents such as colchicine, dapsone, pentoxifylline, levamisole, and thalidomide.

The use of dapsone and colchicine for aphthae prophylaxis has been particularly beneficial in patients with Behçet's disease and complex aphthosis.[70] These agents prevent ulcer formation by suppressing inflammation. Colchicine can cause some gastrointestinal side effects, particularly diarrhea.[71,72] Dapsone is contraindicated in patients with glucose-6-phosphate-dehydrogenase deficiency, as it can cause hemolytic anemia. Another rare potential complication of dapsone is agranulocytosis, so laboratory monitoring is required.[66]

Pentoxifylline is an anti-inflammatory agent used for its immunomodulatory effects. Its mechanism of action involves the inhibition of TNF-α as well as other inflammatory cytokines. A few uncontrolled trials of pentoxifylline have yielded excellent results in the treatment of RAS,[73,74] but a recent controlled, double-blind study showed only modest benefits and suggested that pentoxifylline serves as a non- first-line agent.[73] Additionally, apremilast, a phosphodiesterase-4 inhibitor, is useful for limiting RAS in Behçet's disease; apremilast decreases pro-inflammatory cytokines TNF-α, interferon-gamma, IL-10, and IL-23.[75]

Levamisole has demonstrated the ability to reduce the frequency and duration of ulcers in RAS patients. Although not a common treatment option, levamisole alone and in combination with low-dose prednisolone may be effective therapies.[76] Levamisole normalizes the CD4:CD8 ratio that is aberrant in patients. It is generally given at the first sign of ulceration and has been effective in delaying recurrences. Its side effects include some taste disturbances and nausea, though overall it is well tolerated.[76,77,78]

Thalidomide, a dangerous teratogen reintroduced in 1998 for the treatment of erythema nodosum leprosum, has been proven effective in HIV patients with aphthae, particularly when aphthae are severe.[3] Other studies have shown thalidomide to be effective in immunocompetent patients with Behçet's disease and Crohn's disease.[79] Thalidomide leads to diminished pain, improved oral function, resolution of ulcers, and suppression of recurrences. In vitro studies have documented that thalidomide changes the TNF-α concentration, but the exact mechanism remains unknown.[80,81] In the United States, thalidomide can only be prescribed through a monitoring and registration program, mandated by its teratogenicity and side effects including neuropathy, headaches, and constipation.

Level of evidence

II-2.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.