Are You Confident of the Diagnosis?
Aphthous stomatitis is a common, painful, oral ulcerative condition that is self-healing but recurrent. The onset is typically in childhood and the frequency of recurrences tends to decrease with age. In the most common form, lesions have a subtle 1-2 day prodrome, last 7 to 10 days, and resolve without scarring even in the absence of treatment. Preceding trauma from sharp foods or biting is often cited as an instigating factor.
Characteristic findings on physical examination
On clinical examination, aphthous ulcers present as painful, well-demarcated ulcers with an erythematous ring and pseudomembranous slough at the base (Figure 1) The location, size, configuration and duration can be variable. The softer, mobile, less keratinized surfaces of the mouth are most commonly affected (labial and buccal mucosa, soft palate, unattached gingiva, ventral tongue and floor of mouth).
In simple aphthosis, ulcers are less than 1 cm in size, occur one or two at a time and resolve without treatment in 7 to 10 days without scarring. In complex aphthosis, ulcers may be larger than 1 cm, occur many at a time or in herpetiform clusters and are often slower to resolve, sometimes leaving scars.
Expected results of diagnostic studies
The histopathology of an aphthous ulcer is nonspecific, displaying a mixed, reactive dermal infiltrate beneath a disrupted epithelium (Figure 2). Serologic testing is not diagnostic, but screening is recommended to identify nutritional deficiencies (possible aggravating factors): CBC, ferritin, folate, vitamin B1, vitamin B2, vitamin B6, vitamin B12, magnesium and zinc.
The differential diagnosis includes: herpes simplex, varicella zoster, hand foot and mouth disease, erythema multiforme, bullous disorders, pyostomatitis vegetans, syphilis, lichen planus, lupus erythematosus, celiac disease, oral cancers and systemic diseases (cyclic neutropenia; Behcet’s disease (O’Duffy criteria: aphthous stomatitis plus two of the following – genital aphthosis, uveitis, cutaneous pustular vasculitic lesions, synovitis, meningoencephalitis) ; PFAPA (periodic fever, aphthosis, pharyngitis, cervical adenitis); MAGIC syndrome (mouth and genital ulcers with inflamed cartilage); HIV).
This extended differential is best limited by obtaining a detailed history. If the diagnosis remains unclear, further testing may be helpful. Biopsies for Hematoxylin and eosin (H&E) and direct immunofluorescence are of benefit to rule out bullous dermatoses and cancer.
Serologic screening to rule out other in the differential diagnosis includes: erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), thyroid stimulating hormone (TSH), IgA and IgG tissue transglutaminase (TTG), rapid plasma reagin (RPR), and HIV. A swab sent for polymerase chain reaction (PCR) can identify herpes simplex virus (HSV) or Varicella zoster virus (VZV) infection. Further evaluation may require referral to gastroenterology, hematology or rheumatology.
Who is at Risk for Developing this Disease?
Aphthous ulcers are common, affecting approximately 20% of the population. Children and adults of all races can be affected, but wealthy, nonsmoking, white females under the age of forty are at the highest risk. Prevalence is quite high amongst medical and graduate students. Smoking is inversely associated.
What is the Cause of this Disease?
Aphthous stomatitis is an inflammatory condition of unknown etiology.
Immune mechanisms postulated to play a role in the pathophysiology include both cell-mediated and antibody-mediated processes. There appears to be a genetic predisposition, and a positive family history can be obtained in one-third of patients. Nutritional deficiencies (see above) have been identified in patients, but no causative links to the disease have been identified. Premenstrual flaring is commonly reported.
Systemic Implications and Complications
Aphthous stomatitis most commonly presents as a localized condition without systemic implications. In a minority of cases, aphthous stomatitis presents in association with a hematologic, rheumatologic, infectious, or multisystem disease.
-Cyclic Neutropenia: children, CBC, referral to a pediatric hematologist
-Behçet’s disease: review of systems, full skin exam, referral to ophthalmology and rheumatology
-FAPA (fever, aphthosis, pharyngitis, cervical adenitis): children, complete blood count (CBC), ESR, C-reactive protCRP, strep testing, referral to a pediatrician
-MAGIC syndrome, skin (ear) biopsy, referral to rheumatology
-HIV: HIV testing, referral to infectious disease
Oral Hygiene Products
Sodium Laurel Sulfate-free Toothpaste (Rembrandt Canker Sore Toothpaste, Tom’s of Maine SLS-free toothpastes, plain baking soda)
Topical Medications for Symptomatic Relief
Lidocaine 2% viscous solution, 15ml. Swish and spit every 3 hours as necessary; not to exceed 8 doses in 24 hours
Lidocaine 2% gel applied to the lesions every 3 hours as necessary; not to exceed 8 doses in 24 hours
Sucralfate 1G/10mL solution 10ml two to four times a day
Fluocinonide or clobetasol gel applied two to three times a day
Dexamethasone solution 0.5mg/5ml. swish and spit 5ml two to three times a day
Triamcinolone intralesional injection 0.1ml to 0.5ml of 10mg/ml solution
Over-the-Counter Systemic Treatment
Vitamin B12 1000ug daily
Prescription Systemic Treatments
Prednisone 40-60mg start tapered over 1 to 2 weeks (goal is steroid-sparing therapy)
Colchicine 0.6mg three times a day (often used in combination with Dapsone)
Dapsone 100 to 150mg daily
Pentoxifylline 400mg three times a day
Montelukast 10mg daily
Clofazimine 100mg daily for 1 month then 100 mg every other day
Anti-TNF-alpha Inhibitors – etanercept and adalimumab (for severe and refractory cases given side effects and expense)
Thalidomide (for severe and refractory cases given side effects)
Optimal Therapeutic Approach for this Disease
Simple aphthosis may only require reassurance. If treatment is desired, topical lidocaine can be used to provide symptom relief, and topical corticosteroids can be used at the first sign of a new lesion to decrease lesion severity and duration.
Severe aphthosis typically requires more aggressive management in addition to the above interventions. Colchicine is a simple first-line drug that does not require any blood work. Most patients can tolerate twice daily dosing, and many patients can tolerate three pills daily if dosed one in the morning and two at bedtime.
If colchicine is effective but more improvement is desired, Dapsone can be added with a goal dose of 100-150mg daily. Dapsone does require laboratory screening and monitoring.
If expense (colchicine) or laboratory testing (Dapsone) are limiting factors, pentoxifylline or montelukast are both reasonable options. Both are well-tolerated and neither requires laboratory testing. Because of the natural waxing and waning course of aphthosis and the time to onset of medication effect, it is best to give medications a 3-month trial.
Refractory disease may require consideration of thalidomide or an anti-TNF-alpha Inhibitor. Some physicians feel the expected benefit of these drugs out weighs the risks while others do not. If these drugs are considered, time needs to be reserved for a thoughtful discussion with the patient.
Complex aphthosis is a chronic condition that we attempt to manage, not cure. The natural course is one of waxing and waning. In some cases, there is remission. Patients need to expect long-term treatment. The goal is to identify the minimum medication needed to bring about sufficient comfort and control.
Frequency, duration and severity of lesions can be quite variable and therapies should be titrated accordingly. Patients should be followed on a periodic basis (every 4 to 6 months) to assess disease activity. If episodes decrease and or become less severe, medication doses can be slowly decreased. The possibility of recurrence always remains.
Unusual Clinical Scenarios to Consider in Patient Management
None for simple aphthosis. Several syndromes listed in the differential diagnosis (see “Are you Confident of the Diagnosis?” section, above) may have a host of systemic implications.
What is the Evidence?
Davatchi F, Sadeghi Abdollahi B, Tehrani Banihashemi A, Shahram F, Nadji A, Shams H, Chams-Davatchi, C. “Colchicine versus placebo in Behcet's disease: randomized, double-blind, controlled crossover trial”. Mod Rheumatol. vol. 19. 2009. pp. 542-9. (Controlled study supporting the effectiveness of colchicine.)
Hello, M, Barbarot, S, Bastuji-Garin, J, Chosidow, O. “Use of thalidomide for severe recurrent aphthous stomatitis: a multicenter cohort analysis”. Medicine. vol. 89. 2010. pp. 176-82. (Large study supporting effectiveness of thalidomide and highlighting significant side effect profile.)
Letsinger, JA, McCarty, MA, Jorizzo, JL. “Complex aphthosis: a large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide”. J Am Acad Dermatol. vol. 52. 2005. pp. 500-8. (Proposed treatment ladder based on significant clinical experience.)
Lynde, CB, Bruce, AJ, Rogers, RS. “Successful treatment of complex aphthosis with colchicine and dapsone”. Arch Dermatol. vol. 145. 2009. pp. 273-6. (Large patient cohort showing success with laddered usage of colchicine and Dapsone.)
Messadi, DV, Younai,, F. “Aphthous Ulcers”. Dermatologic Therapy. vol. 23. 2010. pp. 281-90. (Up-to-date, clinically useful review.)
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