What is the appropriate workup and treatment for frequent aphthous ulcers?

Workup for Frequent Aphthous Ulcers

For patients with frequent aphthous ulcers (≥4 episodes per year), initiate a systematic workup to identify underlying systemic causes, starting with complete blood count, iron studies, folate, vitamin B12, fasting glucose, HIV serology, and syphilis serology, while reserving biopsy for ulcers persisting beyond 2 weeks or those with atypical features. 1, 2

Initial Clinical Assessment

Document specific ulcer characteristics to guide workup intensity:

• Size and morphology: Minor aphthous ulcers (<1 cm, heal in 7-14 days), major aphthous ulcers (>1 cm, persist weeks to months), or herpetiform pattern (multiple small ulcers) 3, 4
• Location: Recurrent aphthous ulcers typically appear on non-keratinized mucosa (buccal mucosa, labial mucosa, tongue, soft palate) rather than keratinized surfaces 3, 5
• Duration and frequency: Recurrent aphthous stomatitis (RAS) is defined as ≥4 episodes per year 4, 5
• Associated symptoms: Presence of fever, genital ulcers, eye symptoms, or gastrointestinal complaints suggests systemic disease rather than idiopathic RAS 1, 6

Essential Laboratory Workup

All patients with frequent aphthous ulcers require the following baseline tests to exclude systemic causes: 1, 2

• Complete blood count: Detects anemia, leukemia, neutropenia, or other hematologic disorders that manifest as widespread necrotic ulcers 1, 6, 7
• Iron studies, folate, and vitamin B12: Nutritional deficiencies are common correctable causes 1, 4, 5
• Fasting blood glucose: Hyperglycemia predisposes to invasive fungal infections 1, 6
• HIV antibody testing: HIV infection is an important cause of persistent or severe aphthous ulceration 1, 6, 3
• Syphilis serology: Syphilis can manifest as palatal ulceration 1, 6

Additional Testing for Specific Clinical Scenarios

If bipolar aphthosis (oral and genital ulcers) is present, suspect Behçet's disease—this is the defining clinical feature 1, 4

If gastrointestinal symptoms coexist (diarrhea, abdominal pain, weight loss), screen for inflammatory bowel disease (Crohn's disease, ulcerative colitis) as oral ulcers may be the presenting manifestation 1, 4, 5

If bullous lesions or desquamative gingivitis accompanies ulcers, check serum antibodies (Dsg1, Dsg3, BP180, BP230) for pemphigus vulgaris or mucous membrane pemphigoid 1

If fever accompanies ulcers, add 1-3-β-D-glucan and galactomannan levels to detect invasive fungal infection, particularly in patients with hyperglycemia 6

Biopsy Indications

Perform biopsy with histopathology for: 1, 2

• Ulcers persisting beyond 2 weeks despite appropriate treatment
• Ulcers not responding to 1-2 weeks of initial therapy
• Atypical features (indurated borders, stellate shape, undermined edges)
• Solitary chronic ulcers (to exclude squamous cell carcinoma)
• Suspected autoimmune conditions (include direct immunofluorescence)

Critical pitfall: Inadequate biopsy technique (too small or superficial) misses diagnostic features—ensure adequate depth and size 1, 2

Specialist Referral Criteria

Refer to oral medicine specialist for: 1, 2

• Ulcers lasting >2 weeks
• Ulcers not responding to 1-2 weeks of treatment
• Recurrent, severe, or atypical presentations
• Need for specialized diagnostic procedures including biopsy
• Coordination of multidisciplinary care when systemic disease identified

Critical pitfall: Never rely solely on topical treatments for persistent ulcers without establishing definitive diagnosis, as this delays identification of malignancy, lymphoma, or systemic disease 2, 6

Treatment Approach Based on Workup Results

For idiopathic RAS with negative workup, initiate topical corticosteroids (clobetasol propionate 0.05% gel for localized ulcers or betamethasone sodium phosphate 0.5 mg in 10 mL water as rinse four times daily for widespread ulcers) 6, 3, 5

For nutritional deficiencies identified, correct the specific deficiency (iron, folate, B12) as this may resolve the ulceration 1, 4, 5

For Behçet's disease, colchicine combined with topical steroids constitutes first-line systemic therapy 6, 4

For inflammatory bowel disease-associated ulcers, treat the underlying IBD to resolve oral ulceration 6, 4

For refractory cases not responding to topical therapy, escalate to systemic corticosteroids (prednisone 30-60 mg or 1 mg/kg for 1 week with tapering) or consider colchicine, azathioprine, or TNF-alpha inhibitors for severe cases 6, 3, 5