What is the best treatment approach for a patient presenting with mouth ulcers, considering potential underlying causes such as autoimmune disorders, viral infections, or nutritional deficiencies?

Treatment of Mouth Ulcers

Start with topical corticosteroids as first-line therapy for all mouth ulcers, selecting the formulation based on ulcer location and extent, combined with pain control measures and oral hygiene, escalating to systemic therapy only for refractory or severe recurrent cases. 1, 2

Initial Topical Corticosteroid Therapy

The choice of topical steroid depends on whether ulcers are localized or widespread:

For localized, accessible ulcers:

• Apply clobetasol 0.05% gel or ointment directly to the dried ulcer 2-4 times daily 1, 2
• Alternatively, use triamcinolone acetonide 0.1% paste applied to dried ulcer 2-4 times daily 1, 2

For multiple or widespread ulcers:

• Use betamethasone sodium phosphate 0.5 mg dissolved in 10 mL water as a rinse-and-spit solution 4 times daily 1, 2
• Dexamethasone mouth rinse (0.1 mg/mL) is an alternative option 1, 2

Pain Management (Essential for Maintaining Oral Intake)

Aggressive pain control is critical for quality of life:

• Apply viscous lidocaine 2% topically 3-4 times daily, particularly before meals 1, 2
• Use benzydamine hydrochloride rinse or spray every 3 hours, especially before eating 1, 2
• Consider amlexanox 5% oral paste (topical NSAID) for severe pain 1

Barrier Protection and Oral Hygiene

These measures reduce bacterial colonization and protect ulcerated mucosa:

• Apply mucoprotectant mouthwashes (Gelclair or Gengigel) 3 times daily 1, 2
• Rinse with warm saline mouthwashes daily 1, 2
• Use 0.2% chlorhexidine digluconate mouthwash twice daily as antiseptic rinse 1, 2
• Avoid alcoholic mouthwashes 3

Dietary Modifications

• Eat soft, moist foods served at room temperature or cold 3, 4
• Avoid acidic, spicy, salty, rough, or hot foods 3
• Maintain adequate hydration 3

Second-Line Therapy for Non-Responsive Ulcers (After 1-2 Weeks)

If topical therapy fails after 1-2 weeks of treatment:

• Intralesional triamcinolone injections weekly (total dose up to 28 mg) for persistent localized ulcers 1, 2
• Consider tacrolimus 0.1% ointment applied twice daily for 4 weeks for recalcitrant ulcers 1, 2

Systemic Therapy for Severe or Recurrent Cases

For recurrent aphthous stomatitis (≥4 episodes per year):

• Colchicine is the preferred first-line systemic therapy, particularly effective for patients with erythema nodosum or genital ulcers 1, 2

For highly symptomatic or severe cases:

• Use prednisone/prednisolone 30-60 mg (or 1 mg/kg) for 1 week, then taper over the second week 1, 2
• For pediatric patients: dose at 1-1.5 mg/kg/day up to maximum 60 mg 1

For refractory cases not responding to colchicine or steroids:

• Consider azathioprine, interferon-alpha, TNF-alpha inhibitors, or apremilast 1

When to Refer or Investigate Further

Mandatory referral/biopsy indications:

• Any ulcer persisting >2 weeks despite treatment requires biopsy to exclude malignancy 1, 2
• Ulcers not responding to 1-2 weeks of appropriate treatment 1

Workup for recurrent ulcers:

• Complete blood count, coagulation studies 1
• Nutritional studies: iron, folate, vitamin B12 (28% of recurrent ulcer patients have B1, B2, or B6 deficiency) 5
• Celiac serology 2
• HIV antibody and syphilis serology 1
• Fasting blood glucose 1
• Consider testing for autoimmune blistering diseases (Anti-Desmoglein 1 and 3, Anti-Bullous Pemphigoid Antigen 1 and 2) if clinically indicated 3

Special Considerations for Specific Etiologies

Drug-induced ulcers (e.g., NSAIDs, chemotherapy, immunotherapy):

• Stop the offending medication immediately if possible 4
• NSAIDs are well-documented causes of oral ulcerations 4
• For immunotherapy-related mucositis: 91% present with grade 1-2 severity, 97% have oral ulcers or aphthae 3
• Consider proton pump inhibitor or H2 blocker for gastric acid suppression 3

Behçet's disease:

• Start with topical corticosteroids 1
• Add colchicine for recurrent mucocutaneous involvement 1
• Sucralfate suspension has demonstrated efficacy in RCT for oral and genital ulcers 1
• Progress to azathioprine, interferon-alpha, or TNF-alpha antagonists for refractory cases 1

Critical Pitfalls to Avoid

• Do not taper corticosteroids prematurely before disease control is established 1, 2
• Do not restart NSAIDs without considering risk-benefit ratio if they caused the ulcers 4
• Do not delay biopsy for ulcers >2 weeks duration—squamous cell carcinoma can mimic benign ulcers 1, 6
• Avoid ciclosporine A in patients with neurological involvement due to neurotoxicity risk 1

Treatment Algorithm Summary

1. Start immediately: Topical corticosteroids (clobetasol for localized, betamethasone rinse for widespread) + pain control (lidocaine, benzydamine) + barrier agents 1, 2
2. Add supportive measures: Oral hygiene (saline rinses, chlorhexidine), dietary modifications 1, 2
3. If no improvement in 1-2 weeks: Add intralesional triamcinolone or tacrolimus ointment 1, 2
4. For recurrent cases (≥4/year): Start colchicine as systemic therapy 1, 2
5. For severe refractory cases: Short course of systemic corticosteroids with proper taper 1, 2
6. If persists >2 weeks or no response: Refer for biopsy and investigate underlying causes 1, 2