Orofacial Granulomatosis

Orofacial granulomatosis is a clinical syndrome of persistent or recurrent swelling of the lips, cheeks, face and oral mucosa with non-caseating granulomatous inflammation on biopsy and no systemic cause found. It is a diagnosis made after exclusion of Crohn disease, sarcoidosis, tuberculosis and other granulomatous disease.

Onset is usually in childhood or young adulthood, and the lips are swollen in most. The condition can precede Crohn disease by years.

Pathophysiology. The mechanism is unclear. A delayed type hypersensitivity reaction to dietary or contact antigens in a genetically susceptible person is proposed.

Reported triggers are cinnamaldehyde, benzoates, sorbic acid, chocolate, some dental materials and cosmetics, but proof of cause is lacking in most patients.

Lip swelling that is firm, non-pitting and often episodic at first, becoming persistent. Others have diffuse gingival hyperplasia, cobblestone buccal mucosa, mucosal tags, linear ulcers in the buccal sulcus, fissured tongue, angular cheilitis and facial swelling.

Pain, burning, difficulty eating and psychological distress from appearance are common. Ask about abdominal pain, diarrhoea, weight loss, perianal disease, cough, uveitis and joint symptoms to find a gastrointestinal or systemic cause.

Facial palsy, systemic symptoms or abrupt unilateral swelling needs urgent review, and tongue or floor of mouth swelling with airway compromise is an emergency requiring immediate airway assessment.

• Incisional biopsy of the lip or oral mucosa: non-caseating granulomas, lymphoedema and perivascular lymphocytes. Stain for acid fast bacilli and fungi, and polarise for foreign material.
• Bloods: full blood count, ferritin, vitamin B12, folate, C-reactive protein, serum ACE, calcium, and coeliac serology.
• Faecal calprotectin, and ileocolonoscopy with biopsy when calprotectin is raised or gut symptoms are present.
• Chest radiograph, interferon gamma release assay and tuberculin test when granulomas need tuberculosis excluded.
• Patch testing to a food additive and dental series, and dietary exclusion for 6 to 12 weeks.
• Exclude hereditary angioedema (C4, C1-esterase inhibitor level and function) when swelling is episodic and painless.

Differential diagnosis.

• Crohn disease with oral involvement
• Sarcoidosis
• Melkersson-Rosenthal syndrome and cheilitis granulomatosa
• Angioedema, including hereditary and ACE-inhibitor induced
• Tuberculosis and deep fungal infection
• Foreign body reaction
• Lymphangioma or lymphoedema
• Contact allergy

• Dietary exclusion of cinnamon, benzoate preservatives and other suspect foods and additives for 6 to 12 weeks under dietetic supervision, then reintroduction one item at a time. About half of motivated patients improve. Avoid in children without a dietitian, because of the risk to growth.
• Intralesional triamcinolone acetonide 10 to 40 mg/mL, 0.1 to 0.5 mL at each site, up to a total of 40 mg in one session, repeated at intervals of 4 to 6 weeks. Complications are skin atrophy, local infection and depigmentation, and adrenal suppression is possible with repeated high totals.
• Topical corticosteroid or tacrolimus 0.1% ointment twice daily for mucosal and lip disease, with the cautions for long term use.
• Systemic therapy for severe or progressive disease: prednisolone 0.5 to 1 mg/kg (maximum 40 to 60 mg) orally each morning for 2 to 4 weeks, tapered over a further 4 to 8 weeks, with steroid sparing agents:
  • Azathioprine 2 to 2.5 mg/kg daily after thiopurine methyltransferase testing, with full blood count and liver tests every 2 weeks for the first 2 months, then every 3 months. Avoid allopurinol, and reduce the dose in renal impairment.
  • Methotrexate 7.5 to 15 mg orally once weekly, with folic acid 5 mg once weekly on a different day, full blood count, liver tests and creatinine every 2 weeks initially. Contraindicated in pregnancy.
  • Anti-TNF therapy such as adalimumab 160 mg subcutaneously at week 0, 80 mg at week 2, then 40 mg every 2 weeks, mainly for coexisting Crohn disease or refractory disease. Screen for tuberculosis and hepatitis B first.
• Surgical reduction of the lip or cheiloplasty for persistent deformity after inflammation is controlled.
• Treat Crohn disease or sarcoidosis directly if found.

Special groups. Children need paediatric gastroenterology input, because Crohn disease is more likely, and a dietitian for exclusion diets.

Monitoring. Review at 6 to 8 weeks, then every 3 to 6 months. Repeat symptom screen and calprotectin periodically, because Crohn disease can emerge years later.

Referral and escalation. Refer to oral medicine and gastroenterology. Urgent referral for airway compromise, suspected tuberculosis or malignancy, rapid progression or systemic features.