Behcet's disease or Behcet's syndrome, a rare inflammatory disorder of unknown aetiology can affect many parts of an individual's body. This article outlines its clinical manifestations and throws light on the possible treatment alternatives.

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History of Behcet’s disease

Behcet’s disease also known as Behcet’s syndrome was described in 1937, by Hulusi Behcet. Since then BD has come to be known as a multisystemic inflammatory disorder of unknown aetiology with many cutaneous, gastrointestinal, articular, vascular, cardiopulmonary, and neurological manifestations.

The mucocutaneous lesions of the disease often exhibit the pathergy reaction with the formation of new lesions or aggravation of previous ones following trivial trauma. BD commonly presents as a classical triad composed of recurrent aphthous oral ulcers, genital ulcers and relapsing uveitis.

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Course and treatment

Behcet’s disease is a multisystemic inflammatory disorder of unknown aetiology that commonly presents as a classical triad composed of recurrent aphthous oral ulcers, genital ulcers and relapsing uveitis.

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Aetiology and pathogenesis

The aetiology of BS remains uncertain. Pathogenesis is established when a profound inflammatory response is initiated by an infectious agent in a genetically susceptible host. The disease most commonly presents in the form of recurrent attacks of acute inflammation. The main morbidity of the syndrome is blindness that develops after repeated attacks of ocular inflammation. Involvement of the central nervous system (CNS) and large vessels can be serious, leading to the patient’s death.

BS starts presentation through the oral mucosas in the form of recurrent oral ulcers. Streptococcus in the oral microbiota suggests its important aetiologic role in BS. The onset of BS is triggered by some environmental factors affecting genetically predisposed individuals, as a multifactorial disease. It is well evidenced in the literature that BS is associated with the allele HLA-B51gene (chromosome 6p21).

Immunological alterations have been observed in patients with BS:

• The presence of circulating immune complexes (IC)
• Serum elevation of complement molecules and acute-phase proteins 
• The presence of autoantibodies of the oral mucosa cytotoxic effect of lymphocytes in the oral mucosa cutaneous hypersensitivity
• Exacerbated production of certain cytokines diminished chemotaxis
• The transformation of peripheral lymphocytes
• Increase in the number of CD-4 and CD-8 cells
• Increase in activation of circulating memory T lymphocytes
• Deficient activation of peripheral NK cells
• Polyclonal activation of B lymphocytes

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Clinical manifestations

Recurrent oral ulcers (ROU)

The ulcers are predominantly complex, multiple, appear in lips, cheeks, tongue, gingiva, palate, tonsils and oropharynx. They usually start as a slightly raised, erythematous lesion that ulcerates within 48 hours. Oral ulcers are the first manifestation of BS, and in the majority of patients, the episodes persist for 1 to 8 years before other signs and symptoms of the disease appear.

Genital ulcers

Genital ulcers generally start as papules or pustules that rapidly develop with rounded or oval erosion with a hardened, edematous halo, capable of causing difficulty with walking, dysuria and dyspareunia. In BS, genital ulcers are the most frequent lesion after oral ulcers. They may appear in any location in the genital region, including the groin, perianal and perineal region, may be accompanied by secondary infection. Complications of these lesions are cystic or urethral fistulas. When not infected, genital ulcers usually heal in three weeks.

Cutaneous lesions

Cutaneous lesions include papulopustular lesions (acneiform) or pseudofolliculitis, erythema nodosum, superficial thrombophlebitis, cutaneous ulcers and nodules, cellulitis type lesions, Sweet’s syndrome, gangrenous pyoderma, other rarer lesions, in addition to the pathergy test itself. The papulopustular eruptions (acneiform) appear to be the commonest cutaneous manifestation.

Acneiform lesions may occur in both sexes, however, it would appear that these lesions mainly occur in men, being located on the face, neck and dorsum, and can be associated with trauma. Women generally present with erythema nodosum, which does not ulcerate, but leave a hyperpigmented surface when they heal.

They occur mainly on the internal part of the thighs but can affect other locations, such as genital, axilla, and inframammary areas, interdigital space, perianal and thorax. Cellulitis in BS presents as large, painful, erythematous, edematous lesions that are located mostly in lower limbs, but also in arms and face.

Ophthalmic manifestations

Inflammatory involvement of the eye is considered a serious manifestation of BS. It is the main cause of blindness in BS. It varies from moderate conjunctivitis to vasculitis, atrophy or progressive retinal destruction. It is bilateral in around 90% of cases, and affects the posterior chamber of the eye more severely than the anterior chamber, leading to blindness. Patients experience pain in the eye, blurred vision, and complete or partial loss of sight.

Terminal disease is characterised by venoarterial thrombosis, optic and retinal atrophy associated with complications, such as secondary glaucoma, macular degeneration and cataract.

Joint manifestations

Synovitis, arthritis and/or arthralgia may occasionally occur. These episodes may imitate various joint conditions, from an acute and migratory form of arthritis, as in rheumatic fever, to a chronic form of arthritis resembling rheumatoid arthritis. The joints most commonly affected are the ankles, wrists and knees, and the episodes can last for several days or even weeks.

Neurological manifestations

Acute or chronic neurological disease (Neuro-Behcet or NB) develops in approximately 2 to 30% of the cases and is considered one of the most serious manifestations of BS. The classical manifestation of NB is meningoencephalitis, organic brain syndrome (memory deficit, dementia, apathy, psychomotor agitation, mania, insomnia and delirium) and strokes. Other findings in NB are seizures, sphincter dysfunction, hearing loss, cerebellar, pyramidal and extrapyramidal dysfunction; peripheral and cranial neuropathy and myelopathies.

Vascular manifestations

Vascular involvement is common and affects arteries and veins of all sizes. Arterial manifestations include arteritis with thrombosis, eventually forming aneurysms, which may occur in large-size vessels, such as pulmonary and carotid arteries.

Deep venous thrombosis (DVT) is the most frequent venous manifestation, followed by superficial phlebitis. Other rare vascular manifestations in BS include intracardiac thrombus, coronary artery vasculitis, valvular lesions, aortic aneurysms, pericarditis, endomyocardial fibrosis, and portal hypertension.

Gastrointestinal manifestations

Some patients present with diffuse abdominal pain, chronic colitis, gastric ulcer and pancreatitis. Enteritis may occur in the ileocecal region, presenting perforation initiating morbidity. BS shares many signs and symptoms of inflammatory intestinal disease, such as Crohn’s disease and necrotising ulcerative rectocolitis.

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Differential diagnosis

The disease presents with a number of manifestations that could be confused with the following conditions. It is necessary for the clinicians to rule out the possible differential diagnosis.

• Herpes simplex infection
• Neumann’s bipolar aphthosis
• Reiter’s syndrome
• Systemic erythematosus lupus
• Sweet’s syndrome
• AIDS
• Immunoinflammatory skin diseases (pemphigus, pemphigoid, lichen planus, erythema multiform)
• Sarcoidosis
• Multiple sclerosis
• Steven-Johnson’s syndrome
• Crohn’s disease
• Celiac disease

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Treatment (as recommended by the American Behcet’s Disease Association)

Topical treatments

• Triamcinolone (0.05-0.5%)
• Fluocinolone (0.05-1%)
• Betamethasone (0.1%), in the form of mouthwashes (5 times a day, avoiding mouthwash ingestion)
• Corticosteroids (triamcinolone) in Orabase
• Coadjuvant treatments include lidocaine (2-5%), mouthwashes with chlorhexidine solutions (0.12%) or tetracycline (250mg in 5ml of glycerin)
• Potent corticosteroids (clobetasol propionate) in the form of creams can be beneficial for genital ulcers

Systemic treatment

1. Colchicine (1.0 to 2.0 mg/day)
   1. More effective for erythema nodosum, arthritis, ROU and genital ulcers in women, but only for arthritis in men.
   2. Diminishes the recurrence of ocular attacks.
2. Dapsone (50-100mg/day)
   1. For treatment of mucocutaneous lesions, improving parameters such as the number, size, frequency and duration of ROUs, genital ulcers and cutaneous lesions.
   2. Its most serious side effects are hemolysis, methemoglobinemia and agranulocytosis.
3. Thalidomide (100-300 mg/day)
   1. Effective for oral and genital ulcers, and for cutaneous lesions.
   2. Thalidomide is teratogenic and neurotoxic, and should therefore be used with extreme caution.
4. Pentoxifylline- An anti-TNF agent used to control orogenital ulcerations.
5. Systemic Corticosteroids:
   1. Valuable in the treatment of uveitis (acute stage) and during severe acute episodes of arterial and neurological manifestations, particularly when combined with other immunosuppressant/cytotoxic drugs.
   2. Acute episodes of NB may be treated with oral prednisolone (1 mg/kg) for 4 weeks or until the condition is resolved, or high intravenous doses of methylprednisolone (1g/day) for 3-7 days.
   3. To prevent recurrences, both regimes need to be continued with oral corticosteroid for a minimum of 2-3 months.
6. Azathioprine (1 to 2.5 mg/kg/day)- Reduces the development of the disease and of acute ocular episodes.
7. Methotrexate (7.5-20 mg per week)- Diminishes neuropsychiatric disease progression, has a beneficial action in cutaneous vasculitis and in cases of refractory arthritis.
8. Cyclosporin A (2 to 5 mg/day)- Fast and effective drug for the relief of acute uveitis episodes (preserving the visual acuity of these patients).
9. Tacrolimus- An immunosuppressant agent with activity similar to cyclosporin A; it is better tolerated, helps in the treatment of recurrent uveitis, particularly when cyclosporin is not responsive.
10. Cyclophosphamide- Monthly intravenous pulse therapy with cyclophosphamide (0.75 mg/m of body surface) has been shown to be as effective as cyclosporin in the long term treatment of uveitis but also has shown excellent results in the treatment of neurological and arterial manifestations.
11. Biological therapy
    1. The interferons (IFN) are cytokines with antiviral, antitumoral and immunoregulatory activity, which appear to be effective in the treatment of BS, basically because of their action of inhibiting T lymphocytes and stimulating NK cells.
    2. Interferon-α has demonstrated a partial or complete response in patients with mucocutaneous manifestations and arthropathy.

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Other treatments

1. Correction of haematological iron, vitamin B12 or folate deficiencies.
2. Sulphasalazine at the dose of 2-3 g/day constitutes a treatment option for gastrointestinal lesions and persistent cases of joint manifestations.
3. Surgical intervention may be required in cases of pulmonary artery aneurysms and in cases of severe intestinal involvement, unfortunately with a high rate of recurrence and mortality.

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