BRIEF CLINICAL UPDATE
Farhad Melamed, M.D.
Recurrent aphthous stomatitis affects 20% of the general population and is the most common form of oral ulcerative disease. Also referred to as canker sores when occurring in more solitary lesions, the condition is more commonly seen in females, with a tendency to be seen in the upper socioeconomic classes.1,2
There is no proven etiology for recurrent aphthous stomatitis. Immune-complex mediated vasculitis and autoantibodies against the oral mucosal membranes have been suggested due to the histopathological features. Precipitating factors include trauma, stress, chemical irritants, hormones, and heredity.1 Local trauma frequently leads to non-recurrent solitary ulcers which is different from recurrent aphthous stomatitis. Emotional and physical stress have been implicated in the pathogenesis which is supported by the observation that students and military personnel have a high incidence of oral ulcers.3 Certain foods, including coffee, chocolate, potatoes, cheese, nuts, figs, citrus fruits, and gluten-containing foods, have also been implicated.2 Deficiencies in iron, folate, and vitamin B-12 have been noted in relation to these ulcers.4
L-forms of streptococci are most frequently isolated from aphthous ulcers. It is believed that antibody formation and complement fixation induced by these streptococci may play a major role in the pathophysiology.2 This theory is also supported by the rapid clinical response to topical and systemic therapy with tetracycline, which is very active against streptococci.
Although there is a high correlation of recurrent aphthous stomatitis in identical twins, genetic considerations tend to point to a polygenic inheritance pattern, with multiple factors affecting penetrance. No clear association between recurrent aphthous stomatitis and an HLA antigen has been shown. Immunopathogenetic studies indicate that the ulcerations might be caused by cytotoxic action of lymphocytes and monocytes on the oral epithelium with an unknown trigger.5
Recurrent aphthous stomatitis has been noted in patients with systemic diseases such as inflammatory bowel disease, Crohn\'s disease, HIV and AIDS, and celiac sprue.6 Despite theories that implicate certain viruses such as Coxsackie virus, herpes simplex virus, Varicella zoster virus, Epstein-Barr virus, CMV or adenovirus, no viral associations have been proven thus far.4,5,7
The condition ranges in severity from minor recurrent aphthous stomatitis, characterized by occasional and self-limited ulcerations, to a very debilitating form, called major recurrent aphthous stomatitis, which is seen in about 10% of patients. A third, and much less common, form of the condition is herpetiform aphthous ulceration.
The minor form usually presents in the second decade of life, with lesions decreasing in frequency and severity with age. These ulcerations are usually small well-defined round ulcers with yellow to gray fibrinous pseudomembrane, surrounded by an erythematous border. They heal in about one week without scarring.1
Major aphthous stomatitis, on the other hand, is much more severe, and is present in fewer than 10% of all cases.2 Sutton\'s disease and periadenitis mucosa necrotica recurrens are synonyms for this condition. Larger and deeper ulcers, more frequent outbreaks, severe pain, tender lymphadenopathy, and facial edema characterize this condition. Ulcers can last from weeks to months and, rarely, extend out to years.1 Usually, these ulcers scar as they heal. Commonly presenting around puberty, major aphthous stomatitis is present throughout the patient\'s adult life.2
Herpetiform aphthous ulceration is characterized by multiple recurrent crops of small and painful ulcers throughout the oral cavity. It is unclear whether this is a variety of recurrent aphthous stomatitis that has a predilection for women and a later age of onset or a non-specific representation of other conditions.5
Four stages of development of such ulcers have been described.2 The premonitory stage occurs within the first 24 hours, as patients may feel a tingling or mild irritant sensation. This is followed by the preulcerative stage, notable by red papules surrounded by an erythematous halo. With painful ulceration of the papule begins the ulcerative stage, which may last up to several weeks. The healing stage lasts in proportion to the severity of the ulcers.
As always, a careful history is the first and most important diagnostic step. Elucidation of the timeline, provocative and palliative factors, and association with other symptoms such as ocular, musculoskeletal, or urogenital symptoms is important.
The physical exam should focus on the location and nature of the lesions, in addition to assessing other organ systems for relevant findings. In such patients, the physician must evaluate and rule out other conditions with similar features. Aphthous stomatitis ulcers involve the non-keratinized oral mucosa such as the tongue, floor of mouth, soft palate, and buccal and labial mucosa.1,2,4
Diagnostic evaluation is usually fruitless, unless vitamin deficiencies are highly suspect. Most diagnostic tests are useful in ruling out other etiologies, rather than being specific to aphthous stomatitis.
Herpes simplex virus infection is usually preceded by vesicles and occurs on keratinized mucosa bound to periosteum, such as the hard palate and attached gingiva. Such lesions usually respond to acyclovir, especially in immunocompromized patients.1,4
Shingles and herpangina are other examples of oral vesiculo-ulcer conditions with viral etiologies. Varicella is distinguished by its dermatomal distribution along the respective branch of the trigeminal nerve. Herpangina, caused by the Coxsackie virus, is common in children and usually is seen in the posterior region of the mouth and pharynx.4
Behcet\'s syndrome is characterized by similar ulcerations as discussed above, but also includes uveitis, urethritis, and arthralgia, in addition to skin, vascular, and neurological involvement. These findings usually are not present simultaneously, thus a careful history is integral to the evaluation.1
Crohn\'s disease is an idiopathic chronic inflammatory disease that can involve any part of the gastrointestinal tract. Oral ulcers can be seen, but biopsy reveals characteristic chronic granulomatous inflammation.1
Squamous cell carcinoma should be entertained in the initial presentation of a solitary ulcer that does not resolve in a timely manner. This is of higher concern in the patient with a history of tobacco use and/or alcohol consumption.4
Mouth and genital ulcers with inflamed cartilage characterize MAGIC syndrome. As part of this syndrome, patients can also have fever, pharyngitis, and aphthous ulcers.5
FAPA syndrome was described by Marshall and colleagues based on a group of 12 pediatric patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis.8 Several possible cases have been described in adults, but no definitive tests exist for the diagnosis of this condition, further research is necessary.
Mucocutaneous diseases such as erythema multi-forme, erosive lichen planus, cicatricial pemphigoid, and pemphigus vulgaris should also be considered.1 These conditions are commonly accompanied by typical skin lesions which can be evaluated by biopsy.
Given the unclear etiology of recurrent aphthous stomatitis, no definitive therapy exists. Pain control is the main concern in both minor and major aphthous stomatitis. For patients with major aphthous stomatitis, medication for the promotion of ulcer healing and prevention of future outbreaks should be prescribed. Solitary aphthous ulcers due to local trauma do not require therapy since they are often self-limited.
Patients with aphthous stomatitis suffer moderate to severe pain. For short-term pain relief lasting about 10-15 minutes, a number of oral rinses containing benzocaine and viscous lidocaine are used. For more sustained pain relief lasting up to six hours, zilactin, a topical medication, can be used. Zilactin adheres to the ulcer and forms an impermeable membrane that protects the oral ulcer from trauma and further irritation. Ziladent is a similar product that also contain benzocaine for topical analgesia.1 Others have used betadyne topical solution with a similar effect. Dyclone can also be used to rinse out the mouth just before meals and at bedtime.3 Aphthasol is an amlexanox oral paste similar to zilactin, and it is designed to decrease pain by forming a protective barrier on the ulcer against outside agents that can aggravate the lesion.6
To promote ulcer healing, glucocorticoids, either topically or orally, are the mainstay of therapy. Topical betamethasone-containing syrups and fluocinonide ointment can be used in milder cases and with earlier lesions 1,2 Oral prednisone (up to 15 mg/day) can be prescribed for more severe or progressive disease.1 Therapeutic results may be observed in about one week. It is important to rule out infectious etiologies prior to initiating steroid use.
Thalidomide is a sedative hypnotic that has immunosuppressive and anti-inflammatory properties. It has been used in the treatment of major aphthous stomatitis, as well as Behcet\'s syndrome, erythema nodosum, discoid lupus, and graft vs. host disease. However, its risk of teratogenesis has limited its use.1,6
Chlorhexidine is an antibacterial mouth rinse which promotes healing of ulcers. It has also been noted to reduce the duration of ulcers and prolong the intervals between outbreaks.1,5 However, some believe that the gel preparation, not yet available in the US, is the only effective form.3
Silver nitrate has been described as beneficial in cauterizing the central portion of the ulcer for pain relief.2 Furthermore, some believe that tetracycline works with a similar mechanism while others argue in favor of its anti-streptococcal effects; tetracycline 250 mg in 10 cc syrup is recommended as an oral rinse, for times per day for up to two weeks.
Levamisole has been evaluated multiple times as a possible therapy, given its immunostimulatory effects; however, definitive proof of its efficacy is lacking.5
Colchicine has also been reported to have beneficial effects in the treatment of mucocutaneous conditions. It is believed that this may be due to the drug\'s actions on various leukocyte functions, including microtubular function of PMN leucocytes and adhesion molecule expression.1,5
Pentoxifylline has immunosuppressive actions by interfering with neutrophil adherence and inhibition of lymphocyte activation.5,6 Trental (pentoxifylline) 400 mg three times per day for one month was effective in reducing the number of recurrent aphthous stomatitis episodes for up to 9 months post therapy. No side effects were reported.5
Given the prevalence of aphthous stomatitis, primary care physicians should become familiar with its presentation and management. Oral ulceration could be caused by a variety of diseases, thus physicians need to carefully evaluate patients who present with oral ulcers. Treatment of recurrent aphthous stomatitis should focus on pain management. However, in major aphthous stomatitis, medication may be used to promote ulcer healing and prevent future outbreaks.