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Aphthous Ulcers

Aphthous ulcers are a common and painful problem. Benign aphthae tend to be small (less than 1

cm in diameter) and shallow. Aphthous ulcers that occur in conjunction with symptoms of

uveitis, genital ulcerations, conjunctivitis, arthritis, fever or adenopathy should prompt a searchfor a serious etiology. The lack of clarity regarding the etiology of aphthous ulcers has resulted

in treatments that are largely empiric. These treatments include antibiotics, antiinflammatories,immune modulators, anesthetics and alternative (herbal) remedies.

Aphthous ulcers can be classified into three different types: minor, major and herpetiform.1,2Minor aphthae are generally located on labial or buccal mucosa, the soft palate and the floor of

the mouth. They can be singular or multiple, and tend to be small (less than 1 cm in diameter)

and shallow3 (Figure 1). Major aphthae are larger and involve deeper ulceration. Major aphthae

may also be more likely to scar with healing2 (Figure 2). Herpetiform aphthae frequently aremore numerous and vesicular in morphology. Patients with benign aphthous ulcers should have

no other findings such as fever, adenopathy, gastrointestinal symptoms or other skin or mucous-membrane symptoms.

FIGURE 1.

Minor aphthous ulcer.

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FIGURE 2.

Major aphthous ulcer.

Pathophysiology

The pathophysiology of aphthous ulcers is poorly understood. Histologically, aphthae contain amononuclear infiltrate with a fibrin coating.3 Patients with recurrent aphthae may have alteration

of local cell – mediated immunity. Systemic T- and B-cell responses have also been reported as

altered in patients with recurrent aphthae.2

Etiology

Aphthae more commonly affect young adults, and a familial tendency may exist .3 Paradoxically,smoking offers a somewhat protective effect against recurrent aphthae.2 Other etiologic factors

such as stress, physical or chemical trauma, food sensitivity and infection have been proposed.

Infectious agents such as Helicobacter pylori and herpes simplex virus have been investigated

but have not been consistently found in aphthous ulcers.4 The lack of clarity regarding etiologyhas resulted in treatments that are largely empiric and aimed at symptom reduction.

Differential Diagnosis

Several conditions should be considered in the differential diagnosis when evaluating patients

with recurrent aphthae. A primary consideration is that benign aphthae tend to be smaller and are

more often self-limited when compared to more serious conditions. Major aphthae can beassociated with human immunodeficiency virus (HIV) infection; clinicians should consider HIV

testing when aphthae are large and slow to heal. Table 1 outlines the differential diagnosis of

aphthous ulcers, with distinguishing features.

TABLE 1

Differential Diagnosis of Aphthous Ulcers






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Diagnosis Potential differentiating features

InfectionViral

Herpesvirus Vesicular lesions, Tzank stain positive for inclusion-

bearing giant cells

Cytomegalovirus Immunocompromised patient, biopsy positive formultinucleated giant cells

Varicella Characteristic skin lesions

Coxsackievirus Hand/foot/buttock lesions, typically in childrenTreponemal

Syphilis Risk factors, other skin lesions, RPR/FTA test is positive

FungalCryptosporidium, mucormycosis,

histoplasma

Immunocompromised patient, chronicity, biopsy and

culture positive

Autoimmune

Behçet's syndrome Genital ulceration, uveitis, retinitis

Reiter's syndrome Uveitis, conjunctivitis, HLA B27 arthritisInflammatory bowel disease Recurrent bloody or mucous diarrhea, other GI ulcerations

Lupus erythematosus Malar rash, ANA-positiveBullous pemphigoid Diffuse skin involvement

Pemphigus vulgaris Diffuse skin involvement

Hematologic

Cyclic neutropenia Periodic fever, neutropeniaNeoplasm

Squamous cell carcinoma Chronicity, head/neck adenopathy, biopsy positive

RPR/FTA = rapid plasma reagin/fluorescein treponema antibody test; GI = gastrointestinal;ANA = antinuclear antibody.

Infection-causing ulceration in the mouth should be considered when evaluating patients with

oral symptoms. A common infection, particularly in patients with HIV infection and aphthae, isherpes5 (Figure 3). When Tzank staining is available, a sample from a herpetic lesion will reveal

inclusion-bearing giant cells. Other viral, bacterial, treponemal and fungal agents have the

potential to cause mouth ulcers. Biopsy alone or in conjunction with a culture of lesions or bloodtesting may aid in distinguishing the causative agent.







FIGURE 3.

Herpes stomatitis, found primarily on the alveolar mucosa. Tzank stain of a lesion scraping

revealed inclusion-bearing giant cells.

AUTOIMMUNE DISEASES

Several autoimmune diseases may mimic benign aphthous ulcers. Behçet's syndrome is an

autoimmune vasculitis that causes recurrent oral and genital ulcerations, uveitis and retinitis.Severe aphthae and Behçet's syndrome may be two points on a disease continuum. Non-oral

symptoms of Behçet's syndrome may be present in 43 to 100 percent of patients with recurrent

aphthous ulcers, depending on severity.6 Reiter's syndrome is associated with oral ulcers, uveitis,

conjunctivitis and HLA B27-positive arthritis following nongonococcal urethritis or bacillarydysentery.3 Patients with inflammatory bowel disease, in particular Crohn's disease, may present

with associated mouth ulcerations. Lupus erythematosus, bullous pemphigoid and pemphigus

vulgaris are other diseases that may involve ulceration of the mouth. In all of these conditions,the associated symptoms should be elicited to make a differentiation from benign recurrent

aphthae.

HEMATOLOGIC/ONCOLOGIC DISEASES

Hematologic etiologies should be considered when evaluating recurrent or slow-healing mouth

ulcers. Cyclic neutropenia is associated with mouth ulcers during neutropenic periods.2 Fever

may also be a presenting symptom during these periods. Consideration may be given to blood

count measurement if fever and mouth ulcers regularly occur together. Finally, a neoplasm suchas squamous cell carcinoma must be ruled out when evaluating patients with persistent,

nonhealing mouth ulceration. Office punch biopsy or surgical biopsy may help make thisdistinction. Evaluation of the head and neck for adenopathy is particularly important in this

situation.

Treatment









Treatment for oral aphthae can be divided into five categories: antibiotic, anti-inflammatory,

immune modulatory, symptomatic and alternative (Table 2). The lack of predictability of theefficacy of a particular treatment mirrors the mystery surrounding the etiology of the condition.

TABLE 2

Common Treatments for Aphthous Ulcers

Agent Dosage Evidence for useTetracycline capsule, 250

mg

1 capsule dissolved in 180 mL of

water; rinse with this suspension four

times daily for 4 to 5 days

Randomized, controlled

studies1 support use

Tetracycline syrup, 250

mg per 5 mL5 mL “swish and spit” four timesdaily for 4 to 5 days

As above

Minocycline tablet, 100

mg

1 tablet dissolved in 180 mL of water;

rinse with this suspension twice dailyfor 4 to 5 days

As above

Triamcinolone 0.1% inOrabase (Kenalog in

Orabase)

Apply to dried ulcer two to four timesdaily until healed Randomized, controlledstudies1 show decreased pain

Dexamethasone elixir, 0.5

mg per 5 mL

Swish and spit with 5 mL every 12

hours

As above

Thalidomide 200 mg, one to two times daily for 3to 8 weeks Warning: contraindicated

in pregnancy

Studies in HIV-infected patientsonly7

Amlexanox 5% paste Apply to dried ulcer two to four times

daily

Randomized, controlled

studies9,10 show decreasedsymptoms and faster healing

Viscous lidocaine, 2% Apply to ulcer as needed For brief local pain relief only

Zinc lozenges Suck one lozenge four to six timesdaily

No studies

Vitamin C, 500 mg One tablet, four times daily No studies

Vitamin B complex One tablet, four times daily No studies

l-Lysine, 500 mg One tablet, one to three times daily Studies in herpes only

ANTIBIOTIC THERAPY

Topical and systemic antibiotic treatments are empiric and are used because of a belief that some

as-yet-undiscovered infectious agent is causing the aphthous ulcer. Tetracycline and minocyclineare the agents most commonly used. A 250-mg antibiotic capsule of tetracycline can be

dissolved in 180 mL water and used as a “swish and swallow” or “swish and spit” treatment four times per day for several days in adult patients. Reduction of pain and duration of ulcerations

may result. Tetracycline suspension, 250 mg per 5 mL, can also be used in a similar fashion,with 5 mL swished four times per day. (In children and in women who may be pregnant,

tetracycline should be avoided because of its tendency to discolor teeth.) Minocycline can also

be used this way, with a 100-mg tablet dissolved in 180 mL water and swished twice per day.1The same precautions for children and women apply. In addition, minocycline use can cause

















fetal harm. Therefore, women who are pregnant or who become pregnant while taking the

antibiotic should be informed of the potential for harm to the fetus.

ANTI-INFLAMMATORY AGENTS

Local anti-inflammatory agents may be the most helpful way to speed healing and relievesymptoms in the management of recurrent minor aphthous ulcers. Triamcinolone 0.1 percent

(Kenalog in Orabase) can be applied to ulcers two to four times a day.1 This preparation alsoprovides a protective local coating for the ulcer. Early initiation of this treatment may result in a

more rapid response. The paste can be applied until the ulcer is healed. For more extensive oral

ulceration, dexamethasone elixir, 0.5 mg per 5 mL, may be used as a rinse and expectorated.1Patients should be warned of the potential for secondary fungal infection when using a steroid

rinse. Systemic steroids are generally not recommended in the management of aphthous ulcers,

although they may be helpful in the management of conditions that mimic aphthous ulcers.

IMMUNE MODULATORS

Immune modulators used for the management of aphthous ulcers have been investigated most

thoroughly in patients infected with HIV. Aphthous ulcers in HIV-infected patients may have

extremely protracted healing times, up to months. Thalidomide (Thalomid) is the agent mostfrequently used for management of aphthous ulcers that cause severe pain with eating.

Thalidomide in a dosage of 200 mg once to twice daily for three to eight weeks yields a fasterhealing rate than placebo.7,8 Thalidomide is contraindicated in non-HIV – infected patients

because of its potential for significant side effects and teratogenicity.

Amlexanox 5 percent paste (Aphthasol) has been examined in several studies of the treatment of

aphthous ulcers. The paste was applied to ulcers two to four times a day.9 Healing time was

improved with this agent. In one large study, 21 percent of patients achieved complete healing atthree days compared with 8 percent of untreated patients.10

OTHER AGENTS

Other strategies exist for local and systemic symptom relief in patients with aphthous ulcers.

Pain relief may be achieved with 2 percent viscous lidocaine applied with a cotton swab several

times daily, as needed.1,11 Over-the-counter benzocaine preparations (e.g., Anbesol and Oragel)may also be used. Over-the-counter agents such as Orabase or Zilactin-B coat aphthous ulcers

and provide local protection.11 Brief anesthesia may be obtained with the application of a silver

nitrate stick, although the application itself is quite painful. Silver nitrate may cause more local

necrosis and, ultimately, delayed healing. Finally, the combination of over-the-countermagnesium hydroxide antacid and diphenhydramine hydrochloride (5 mg per mL), mixed half

and half, will bring about some symptom relief .1 A 5-mL dose of the mixture can be swished

and swallowed four to six times a day. Systemic nonsteroidal anti-inflammatory agents or

acetaminophen may provide some analgesia when ulcers are very painful.

ALTERNATIVE AGENTS























Sucking on zinc gluconate lozenges is anecdotally reported to provide local relief and speeding

of healing time for aphthous ulcers. Vitamin C, vitamin B complex and lysine may speed healingwhen taken orally at the onset of lesions. Sage and chamomile mouthwash, created by infusing

equal amounts of the two herbs in water, may be helpful when used four to six times a day.

Echinacea is reported to speed healing, perhaps through its immune modulatory effect. Carrot,

celery and cantaloupe juices also have been reported as helpful complementary agents.12 Noneof these agents has been studied in randomized controlled trials.

Final Comment

Aphthous ulcers are a poorly understood clinical entity that cause significant pain in otherwise

healthy patients. Several agents are helpful in the management of aphthous ulcers, includingantibiotics, antiinflammatories, immune modulators, anesthetics and alternative products. When

ulcers are slow to heal or if associated systemic symptoms are present (e.g., uveitis, arthritis,

fever, adenopathy), other, more serious conditions should be ruled out.

The Author

DAVID R. MCBRIDE, M.D., is the medical director of the Lynn Community Health Center in

Lynn, Mass. He is also a clinical instructor in the departments of family medicine at Boston

University School of Medicine and Tufts University School of Medicine. Dr. McBride received

his medical degree from the University of Pittsburgh (Pa.) School of Medicine and completed aresidency in family practice at York (Pa.) Hospital.

Address correspondence to David R. McBride, M.D., Lynn Community Health Center, 269

Union St., Lynn, MA 01901. Reprints are not available from the author.

REFERENCES

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2. Freedberg IM. Fitzpatrick's dermatology in general medicine. 5th ed. Vol 1. New York, N.Y.:McGraw-Hill, 1999.

3. Cotran RS, Kumar V, Robbins SL. Robbins pathologic basis of disease. 4th ed. Philadelphia:

Saunders, 1989:817.

4. Chapman MS, Cimis RJ, Baughman RD. Lack of association between aphthous ulcers andHelicobacter pylori [Letter]. Arch Dermatol. 1998;134:1634 – 5.

5. Bartlett JG. The Johns Hopkins Hospital guide to medical care of patients with HIV infection.8th ed. Baltimore: Williams & Wilkins, 1999:345.





6. Verpilleux MP, Bastuji-Garin S, Revuz J. Comparative analysis of severe aphthosis and

Behçet's disease: 104 cases. Dermatology. 1999;198:247 – 51.

7. Jacobsen JM, Greenspan JS, Spritzler J, Ketter N, Fahey JL, Jackson JB, et al.

Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency

virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. N Engl J Med . 1997;336:1487 – 93.

8. Ball SC, Sepkowitz KA, Jacobs JL. Thalidomide for treatment of oral aphthous ulcers in

patients with human immunodeficiency visus: case report and review. Am J Gastroenterol.

1997;92:169 – 70.

9. Greer RO, Lindenmuth JE, Juarez T, Khandwala A. A double-blind study of topically

applied 5% amlexanox in the treatment of aphthous ulcers. J Oral Maxillofac Surg.1993;51:243 – 9.

10. Binnie WH, Curro FA, Khandwala A, VanInwegan RG. Amlexanox oral paste: a noveltreatment that accelerates the healing of aphthous ulcers. Compend Cont Educ Dent .

1997;18:1116 – 8,1120 – 2, 1124 passim.

11. Grimes RM, Lynch DP. Frequently asked questions about the oral manifestations of

HIV/AIDS. JAMA HIV/AIDS Information Center. Accessed April 2000: http://www.ama-

assn.org/special/hiv/treatmnt/updates/oral.htm#q2.

12. Strohecker J, ed. Alternative medicine: the definitive guide. Fife, Wash.: Future Medicine,

1995:264.

http://www.ama-assn.org/special/hiv/treatmnt/updates/oral.htm#q2




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