Behcet's disease: causes, symptoms, diagnosis, treatment, and prognosis

Behcet's disease, also known as Behcet's syndrome, silk route disease, or oculo-oral-genital syndrome, is a multi-system, recurrent, chronic autoimmune disease mainly characterized by vasculitis. Common clinical manifestations include recurrent oral ulcers, ocular inflammation, genital ulcers, and skin lesions. Blindness, involvement of the nervous system or digestive system, venous thrombosis, and aneurysms are the most severe manifestations of the disease.


Causes

The etiology and pathogenesis of the disease are still not very clear, and may be related to immunity, heredity, infection, and environment.

HLA-B51 is a major risk factor. HLA-B51 allele is >15% in patients in Europe, the Middle East, and the Far East, but few or absent in Africa, Oceania, and South America.


Signs and Symptoms

The disease can occur in all ages ranging from 4 to 70 years, but mainly invades young adults aged 25 - 35 years, with a male to female ratio of 0.77:1. The disease is generally chronic, with mild systemic symptoms, such as fever, fatigue, anorexia, headache, and arthralgia.

Recurrent oral ulcers

Recurrent oral ulcers occur in almost all patients, and are the initial manifestation in most patients. The condition occurs at least three times a year and is in various parts such as the tongue, lips, gingivae, buccal mucosa, and soft palates. The initial manifestations are small red nodules, and then blisters or papules occur, developing into painful ulcers in 48 hours, with a diameter of 2 - 3cm, healing spontaneously in 1 - 2 weeks.

Recurrent genital ulcers

Generally, the condition is preceded by the oral lesions, and the incidence rate is 75%. The manifestations are similar to those of oral ulcers, mainly in the vulva and vagina in females and in the scrotum and penis in males, as well as in the glans, anus, and cervix. Pain in males is more severe than in females. In general, the ulcers heal in 1 - 3 weeks, leaving scars, and the frequency of recurrent attacks is lower than that of oral ulcers.

Ocular lesions

60% - 80% of patients have ocular involvement, and common lesions are uveitis, retinal vasculitis, optic atrophy, vitreitis, and fundus hemorrhage. Anterior uveitis or iridocyclitis may or may not be accompanied by empyesis. Posterior uveitis and retinal vasculitis are the main causes of impaired vision. Repeated ophthalmia can cause serious visual impairment or even blindness. Ocular involvement in males is more common and more severe than in females. The main clinical manifestations are blurred vision, hypopsia, eyeball congestion, eyeball pain, photophobia, foreign body sensation, and eye floaters. The ocular lesions cause blindness in 33% - 44% of patients.

Skin lesions

The incidence rate is 56% - 99.1%, and the skin lesions are diverse. There are erythema nodosum, pseudofolliculitis, acneform folliculitis, and non-specific skin allergies. Erythema nodosum is the most common, mostly in the calves symmetrically, and is manifested by round or oval, red, raised, tender, subcutaneous nodules, with solid texture, usually relieving spontaneously within one month. Folliculitis with or without pus is also common and similar to acne that occurs during puberty.

Arthritis

Arthritis is seen in 30% - 60% of patients. Various sized joints can be involved, often asymmetrical single or few arthralgia, but multiple joint involvements are also visible. The most common involvement is knee joint, followed by the ankle, wrist, and elbow joints, mostly transient. The red and swollen joints are less common, and dysarthrosis is rare. There are not obvious abnormalities or only mild lesions in X-ray examinations. Synovial biopsy reveals polymorphonuclear or mononuclear cell infiltration. Sacroiliac joints are occasionally involved, and even the spine can be affected. However, arthritis is self-limiting in the disease.

Nervous system lesions

The incidence rate is about 30%, more common in males. The condition is usually severe and occurs 1 - 3 years after onset. Lesions in the central nervous system are more common than in the peripheral nerves, and the latter is generally mild. The manifestations are headache, vertigo, disturbance of consciousness, mental disorders, meningeal irritation, epilepsy, lower limb weakness, numbness, and sensory disturbance. Nervous system lesions are one of the serious complications of the disease, with high recurrence rate, with poor treatment effect, and are the main cause of death in this disease.

Digestive tract lesions

Lesions can occur in any part of the digestive tract, but more common in the ileocecal area, followed by the colon and stomach. Multiple ulcers are deep or superficial, and deep ulcers can cause gastrointestinal perforation. Common clinical symptoms are right lower quadrant pain, nausea, vomiting, abdominal distension, gastrointestinal hemorrhage, and acute abdomen.

Cardiovascular involvement

The incidence rate is 10% - 37%. Various arteries and veins can be involved, but involved veins are more common, mainly venous thrombosis. Large blood vessels involvement is characterized by arterial and venous obstruction, aneurysm, and varices. Superior or inferior vena caval obstruction syndrome is common in venous obstruction. Arterial involvement can form aneurysms, mostly single aneurysm, more common in the aorta, abdominal aorta, and thoracic aorta. Arterial occlusion is less common. However, renal artery stenosis can cause renal hypertension. Cardiovascular vasculitis can affect the heart muscle, valves, and conduction system, and palpitations, angina, and arrhythmia can occur. The involvement of blood vessels is also an important cause of death.

Other manifestations

Pulmonary manifestations are less common, mainly hemoptysis, and may be caused by the bronchial fistula derived from pulmonary aneurysms. In addition, cough, pleurisy, pulmonary aneurysm, pulmonary embolism, and tracheobronchial ulcers can occur. Intermittent proteinuria and hematuria may occur in the renal involvement. Epididymitis manifested by testicular pain and swelling is present in 10% of patients, persisting for 1 - 2 weeks, and can be recurrent. In addition, some patients present with high fever, fatigue, anorexia, and polyhidrosis during acute exacerbations, as well as systemic lymphadenopathy. Long-term low fever is not uncommon.


Histopathology

Perivascular lymphocyte and mononuclear cell infiltration, IgG, IgM, and C3 deposition in the vascular wall, thrombosis in the large vein, and aneurysm due to vascular wall degeneration and necrosis can be seen. Vasculitis has exudative and proliferative changes. The exudative changes are characterized by luminal congestion, vascular wall edema, endothelial cell swelling, and fibrin deposition. Proliferative changes are manifested by proliferation of endothelial cells and adventitial cells, thickening of the vascular wall, and sometimes granuloma formation.


Diagnosis

Prime diagnostic considerations include:

  • Repeated oral ulcers (affirmative aphthous ulcers or sore ulcers at least three episodes a year)

Subprime diagnostic considerations include:

  • Repeated genital ulcers
  • Ocular lesions (anterior or posterior uveitis, retinal vasculitis, vitreous opacity)
  • Skin lesions (erythema nodosum, pseudofolliculitis, purulent papules, post-pubertal acneform nodules)
  • Positive pathergy reaction

If there are one prime and at least 2 subprime diagnostic considerations, the disease can be diagnosed.


Treatment

Topical glucocorticoids can temporarily relieve the ocular and most oral symptoms. However, topical or systemic glucocorticoids cannot change the number of recurrences of this disease. In few patients with severe uveitis or central nervous system involvement, large doses of hormones such as prednisone 60 - 80 mg/d orally are effective.

Anti-TNF drugs appear to be effective against a variety of symptoms, including gastrointestinal manifestations and ocular lesions such as severe refractory uveitis, and can reduce the number of episodes. In the case of severe gastrointestinal and ocular symptoms, anti-TNF drugs can be used in combination with other drugs such as azathioprine. In particular, infliximab has the advantage of rapid onset.

Immunosuppressive agents, including anti-TNF agents, can improve the prognosis of patients with vascular involvement. Immunosuppressive agents help prevent recurrence of venous thrombosis, but it is unclear whether anticoagulant therapy is effective. Anticoagulant therapy is contraindicated in patients with pulmonary aneurysms.

Mucosal lesions

Mucosal lesions can be treated symptomatically with topical hormone drugs, local anesthetics, and sucralfate.

Colchicine 0.6mg orally twice a day can reduce the frequency and severity of oral or genital ulcers and may be effective for erythema nodosum and arthralgia.

Apremilast is an oral phosphodiesterase-4 inhibitor that can reduce oral ulcers and relieve pain.

Thalidomide 100 - 300mg orally once a day can treat oral, genital, and skin lesions. However, once the treatment is discontinued, the lesions may relapse.

Subcutaneous anti-TNF drugs such as etanercept 50mg once a week or 25mg twice a week can inhibit cutaneous and mucosal lesions. If colchicine is not effective, etanercept can be given. Sometimes other anti-TNF drugs such as infliximab and adalimumab can be used in place of etanercept.

If colchicine is ineffective, interferon α-2a 6,000,000 units 3 times a week can also be given.

Ocular lesions

Azathioprine 2.5mg/kg once a day protects vision and prevents new ocular lesions. Azathioprine is also effective for skin and mucosal lesions and multiple arthralgia.

Patients with severe ocular symptoms can take orally cyclosporine 5 - 10 mg/kg once a day. Cyclosporine and azathioprine can be combined to treat refractory uveitis.

Interferon α-2a 6,000,000 units intravenously 3 times a week and infliximab (tumor necrosis factor inhibitor) 3 - 10 mg/kg intravenously on the 0th, 2nd, and 4th week followed by every 8 weeks have a certain effect for patients with ocular lesions.

Refractory or life-threatening diseases

For patients with refractory or life-threatening diseases such as pulmonary aneurysms and central nervous system involvement, cyclophosphamide and chlorambucil can be used. For patients with severe neurological manifestations, cyclophosphamide has a longer event-free survival time than azathioprine.

Surgical treatment

Intestinal perforation and intestinal fistula require surgical treatment. Due to the irregular distribution of ulcers, surgical excision may not be complete, and there may be recurrence after surgery. Therefore, the medical treatment should be continued.


Prognosis

The typical manifestations are a chronic process that aggravates and alleviates alternately. The prognosis in young adults is often poor. Patients with HLA-B51 allele have high risk. In the early stages of the disease, mucosal, cutaneous, and oral lesions and arthralgia are often exacerbated. The central nervous system and large blood vessel involvements occur usually in the late stage. Due to nervous system, blood vessel, and gastrointestinal involvement, death may occasionally occur. Young patients and those with arterial disease and numerous sudden symptoms are at high risk. Most patients eventually enter the remission period.