Behçet's Disease and Recurrent Aphthous Stomatitis

Behçet's Disease (Behçet, 1937) and Recurrent Aphthous Stomatitis

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Behçet's disease (BD) is a chronic multisystem disorder characterized mainly by a triad of (1) recurrent aphthous stomatitis (RAS), (2) genital ulcers, and (3) ocular lesions.

BD more commonly affects individuals of Mediterranean origin, from the Middle East, China, Korea and Japan. There is an association with HLA-B5 and HLA-B51.

Clinical Manifestations:

I. Major criteria:

Recurrent aphthous stomatitis (RAS): in 90%-100% of cases.
Recurrent painful genital ulcers that tend to heal with scars: in 64%-88% of cases.
Ocular lesions: Uveitis with conjunctivitis (early) and hypopyon (late), retinal vasculitis (posterior uveitis) that may result in blindness, iridocyclitis and optic atrophy.
CNS lesions: meningoencephalitis, cerebral infarction, psychosis, cranial nerve palsies, cerebellar and spinal cord lesions, hemi- and quadriparesis.
Skin lesions: erythema nodosum, papulopustular lesions and acneform nodules. Pathergy test: at the site of a needle puncture a pustule surrounded by erythema may appear in some, but not all, patients.

II. Minor criteria:

Arthralgia: large joint arthropathies that are subacute, non-migratory, self-limiting and non-deforming
Superficial or deep migratory thrombophlebitis, especially of lower limbs.
Intestinal lesions: inflammatory bowel disease with discrete ulcerations.
Lung affection: pneumonitis.
Haematuria and proteinuria.

Histopathology:

The common denominator in all systems is vasculitis, usually leucocytoclastic vasculitis.

Pathogenesis:

Viral, immunological, genetic, and ecological causes have been postulated, but the evidence is still inconclusive for any of these.

There are many immunological findings in BD:

The presence of circulating autoantibodies against mucous membranes.
Increased levels of circulating immune complexes, the highest levels being in patients with systemic manifestations.
Demonstration, by DIF, of immunoglobulins and complement deposition within and around blood vessel walls or in the subepithelial zone.
Decreased T-helper (T4) : T-suppressor (T8) ratio.

Treatment:

Topical tetracycline mouthwash is the drug of choice for oral ulcers in BD. Topical steroids and anaesthetics may be used for oral lesions.
Systemic treatment includes corticosteroids, azathioprine, cyclophosphamide, colchicine, dapsone, thalidomide, cyclosporine, levamisole, or chlorambucil.

Differential diagnosis of BD:

I. Other oculomucocutaneous syndromes:

	Main lesions
Disease	Oral and genital	Ocular	Skin
1. Behçet's disease	Aphthae	Uveitis	Erythema nodosum
2. Sweet's syndrome	Aphthae	Conjunctivitis, episcleritis	Inflamed tender papule or nodule
3. Erythema multiforme	Erosions	Erosions	Target (iris) lesions
4. Cicatricial pemphigoid	Bullae, erosions	Erosions with scarring	Occasional dome-shaped bullae
5. Pemphigus	Erosions	Erosions	Multiple flaccid bullae
6. Reiter's syndrome	Ulcers	Conjunctivitis	Keratoderma blenorrhagica

Other oculomucocutaneous syndromes: ulcerative colitis, herpes simplex, syphilis, lupus erythematosus and mixed connective tissue disease.

II. Other causes of recurrent aphthous stomatitis (RAS):

RAS is a common disease which probably afflicts at least 20% of the population. It is characterized by recurring episodes of ulcers, each lasting from 1 to about 4 weeks before healing. Aphthae typically are small, round or ovoid ulcers with a circumscribed margin, erythematous halo and a yellow grey floor.

Aetiology of RAS:

Behçet's disease.
Haematinic deficiency: in 10%-20% of cases; deficiencies of iron, folic acid or vitamin B12.
Gastrointestinal disease: pernicious anaemia, coeliac disease and dermatitis herpetiformis (rare in DH), Crohn's disease and ulcerative colitis.
Endocrine factors: In some women, RAS are clearly related to a fall in progestogens in the luteal phase of the menstrual cycle.
Immunological factors: There is no evidence that RAS is an autoimmune disease. However, CMI mechanisms may be involved in the pathogenesis of RAS. There may be cross-reacting antigens between the oral mucosa and microorganisms such as streptococcus sanguis or its L form. Immunodeficiency: A few RAS patients have an immune defect such as AIDS.
Genetic factors: There is a positive family history in 1/3 of RAS patients. There is increased frequency of HLA-A2, A11, B12 and DR2 in RAS patients.
Trauma: orthodontic appliances and thermal injury ('pizza burn'), certain foods.
Stress and cessation of smoking may play a role.
Acrodynia (Pink disease): Oral and perioral ulceration, hypersalivation, gingivitis and early tooth loss are features of acrodynia caused by mercury poisoning, now rarely seen.
Oculomucocutaneous syndromes: (see table above)
Other causes: (see table below)

Other causes of oral ulcers

Viral infections: Herpes simplex stomatitis, chickenpox and herpes zoster, hand, foot and mouth disease, herpangina (Coxsackie viruses), infectious mononucleosis (EBV) and CMV

Bacterial infections: Tuberculosis, syphilis, oropharyngeal gonorrhoea and acute necrotizing gingivitis (mixed, mainly anaerobic, flora)

Fungal infections: Blastomycosis, coccidioidomycosis, cryptococcosis and histoplasmosis

Skin diseases: Erosive lichen planus, epidermolysis bullosa acquisita

Oral squamous cell carcinoma and other oral malignant primary or metastatic neoplasms

Leukaemia and neutropenia

Vasculitis, e.g. Wegener's granulomatosis

Cytotoxic agents as methotrexate

Irradiation of oral mucosa

There are three main clinical types of RAS:

	Minor aphthous ulcers	Major aphthous ulcers	Herpetiform ulceration
Age of onset	Childhood or adolescence	Childhood or adolescence	Young adults
The lesions	Up to about 6 ulcers, 2-4 mm each, on the lips, cheecks, ventrum of tongue and floor of mouth; uncommon on gingiva, palate or dorsum of tongue	Up to about 6 ulcers, 10 mm each, found on any area of oral mucosa, including dorsum of tongue or palate	10-100 ulcers, initially tiny: 1-2 mm but ulcers coalesce, on any site but often on ventrum of tongue
Pain	Minimal symptoms	More painful	Extremely painful
Duration of each ulcer	Up to 10 days	Up to 1 month	Up to 1 month
Other comments	The most common type of aphthae, little or no evidence of scarring	May heal with scarring	Affect females predominantly. Similarity to herpetic stomatitis gave herpetiform ulceration its name, but there is no evidence that HSV is involved.

Treatment of RAS:

Exclude systemic diseases and treat predisposing factors.
Topical tetracycline mouthwash, 0.2% aqueous chlorhexidine gluconate mouthwash.
Topical steroids in Orabase four times daily.
Thalidomide in doses of up to 300 mg daily (especially in major aphthae), dapsone, colchicine.

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