Behcet’s disease (BD) is a systemic, chronic, vasculitic inflammatory disease with recurrent oral ulcers, genital ulcers, ophthalmia, and skin lesions, and may also involve blood vessels, the nervous system, the gastrointestinal tract, the joints, the lungs, the kidneys, and the epididymis, etc. The prognosis is good for the majority of patients, but poor for those with ocular, central nervous, and large blood vessel involvement. EBV, herpes simplex virus, streptococcal and tuberculosis infections, as well as immunogenetic factors (HLA-B51) may be associated with the development of the disease. About half of the patients are positive for anti-human oral mucosal antibodies and have circulating immune complexes. Disproportionality of peripheral blood lymphocyte subsets, inverted CD4+/CD8+ ratio, lack of CD45RA+ cells, and increased lymphocyte autocrine TNF-α, IL-6, and IL-8, as well as IL-1β and soluble IL-2 receptor in the patients suggest that there are abnormalities of auto-cellular and humoral immunity in the disease, but cellular immune disorders are more closely related to the disease. Unlike other vasculitis diseases, it involves major, medium, small and microvessels throughout the body, with small vessels and veins being the most involved. Histopathologic changes are perivascular lymphoid and mononuclear cell infiltration, IgG, IgM, and C3 deposits may be present in the vessel wall, venous thrombosis, and hemangiomas formed in large arteries due to degeneration and necrosis. Vasculitis has both exudative and proliferative lesions. Exudative changes are hemorrhage in the lumen of the vessel, edema of the wall, swelling of the endothelial cells, and fibrin deposition, while proliferative lesions are hyperplasia of the endothelial cells and tunica albuginea cells, thickening and stenosis of the vessel wall, and sometimes granuloma formation. The disease has a high incidence in East Asia, the Middle East and the Mediterranean region and is known as Silk Road disease. There is no precise information about the incidence in China, and the disease can occur at any age, with a prevalence of 16 to 40 years old. In China, the majority of women, male patients with vascular, neurological and ocular involvement more than women and serious condition. Clinical manifestations] All systems of the body can be affected, but rarely multiple clinical manifestations occur at the same time. Sometimes patients need to go through several years or even longer before various clinical signs and symptoms appear successively. 1.Oral ulcers Almost all patients have recurrent, painful oral ulcers similar to aphthous ulceration (Aphthous ulceration, Aphthous ulceration), and most of the patients have this disease as the first symptom. Aphthous ulceration can occur in any part of the mouth, mostly located on the edge of the tongue, cheeks, lips, soft palate, pharynx, tonsils and other places. Can be single, can also appear in batches, is the size of a grain of rice or soybean, round or oval, the edge is clear, the depth varies, there is a yellow cover at the bottom, surrounded by a clear edge of the red halo accompanied by pain. About 1 to 2 weeks after the self-subsidence without leaving scars. In severe cases, the ulcers are deep and large and slow to heal, occasionally leaving scars. Recurrent mouth ulcers are the most basic symptom necessary for the diagnosis of this disease. 2, genital ulcers about 75% of patients with genital ulcers, lesions and oral ulcers are basically similar. However, the number of occurrences is less. The ulcers are deep and large, with severe pain and slow healing. The affected parts are vulva, vagina, perianal, cervix, scrotum and penis. Vaginal ulcers may be painless with only increased discharge. Some patients may cause hemorrhage or scrotal vein wall necrosis rupture bleeding due to deep ulcers. 3.Ophthalmia About 50% of patients are involved, both eyes can be involved. Ocular lesions can appear months or even years after the onset of the disease, and its manifestations are blurred vision, vision loss, eye congestion, eye pain, photophobia and tearing, foreign body sensation, mosquitoes and headache. It usually presents with a chronic, recurrent, progressive course. Eye involvement causes blindness in up to 25% of cases and is the leading cause of disability in this disease. The most common and severe ocular lesion is uveitis. Anterior uveitis, i.e. iridocyclitis, may or may not be accompanied by pus in the anterior chamber, whereas posterior uveitis and uveitis are the main causes of visual impairment. All the rest of the tissues of the eye can be involved, with keratitis, herpetic conjunctivitis, scleritis, choroiditis, retinitis, optic nerve papillitis, necrotizing retinal vasculitis, and fundus hemorrhage. In addition there may be lens hemorrhage or atrophy, glaucoma, and retinal detachment. The edema of the optic disc alone suggests cerebral venous thrombosis, and intracranial vascular lesions caused by leukoaraiosis can lead to visual field defects. 4, skin lesions, high incidence of skin lesions, up to 80% ~ 98%, a variety of manifestations, nodular erythema, herpes, papules, acne-like rash, erythema multiforme, cyclic erythema, necrotizing tuberculosis rash-like damage, herpetic necrotizing vasculitis, Sweet’s disease-like lesions, septicemia and so on. A patient may have one or more of these lesions. The skin signs with special diagnostic value are nodular erythema-like lesions and inflammatory reaction to tiny trauma (pinprick). 5, joint damage 25% to 60% of patients have joint symptoms. The manifestation is relatively mild limited, asymmetric arthritis. It mainly involves knee joints and other large joints, and HLA-B27 positive patients may have sacroiliac joint involvement, which is similar to ankylosing spondylitis. 6.Neurological damage, also known as neuroleukodystrophy, the incidence rate is about 5%~50%. It often appears several months to years after the disease, and a few (5%) may be the first symptom. Clinical manifestations vary according to the site of involvement. Involvement of the central nervous system is more common, including headache, dizziness, Horner’s syndrome, pseudobulbar palsy, respiratory disturbances, epilepsy, ataxia, aseptic meningitis, optic papilloedema, hemiplegia, aphasia, paraplegia of different degrees, urinary incontinence, bilateral lower limb weakness, sensory disturbances, impaired consciousness, and psychiatric disorders, etc. Peripheral nerve involvement is less common. Peripheral nerve involvement is less common, accounting for about 10% of central lesions, and the manifestations are milder, with only numbness and weakness of the limbs and peripheral-type sensory disturbances. In addition, cerebral thrombosis should be considered when non-meningitis-type headache, vomiting, and increased cranial pressure occur. Neurological damage also has the tendency of alternating episodes and remission, and may have multiple site involvement at the same time. Most patients have poor prognosis, especially brainstem and spinal cord damage is one of the main causes of disability and death in this disease. 7, digestive tract damage, also known as intestinal leukosis. The incidence rate is 10%~50%. The whole digestive tract from the mouth to the anus can be involved, and the ulcers can be single or multiple, with different depths, which can be seen in the lower esophagus, stomach, distal ileum, ileocecal part, ascending colon, but the ileocecal part is more common. Clinical manifestations may include epigastric fullness, belching, dysphagia, middle and lower abdominal distension, vague pain, paroxysmal colic, diarrhea, black stools, constipation and so on. In severe cases, there may be perforated ulcers and even death due to complications such as hemorrhage. Intestinal leukoaraiosis should be noted with inflammatory bowel disease and non-steroidal anti-inflammatory drugs (NSAIDs) caused by mucosal lesions to distinguish, the right lower abdominal pain should be noted with appendicitis to distinguish, often due to clinical cases of non-healing of wounds after surgery. 8, vascular damage The basic lesion of this disease is vasculitis, the whole body large and small blood vessels can be involved, about 10% to 20% of patients with large and medium-sized vasculitis, is the main cause of death and disability. When the arterial system is involved, the elastic fiber of the arterial wall is destroyed and the endothelial fiber of the arterial wall is proliferated, resulting in arterial stenosis, dilatation or aneurysm, and the corresponding clinical manifestations appear, such as dizziness, headache, syncope and pulselessness. Aneurysms on the aortic arch and its branches are at risk of rupture. The venous system is more commonly involved than the arterial system, and about 25% of patients develop superficial or deep migratory thrombophlebitis and venous thrombosis, resulting in stenosis and embolization. Involvement of the inferior vena cava and lower extremity veins is more common, and Budd-Chiari syndrome, ascites, and swelling of the lower extremities may occur. Superior vena cava obstruction may be characterized by maxillofacial and neck swelling and elevated venous pressure in the upper extremities. Superficial phlebitis may cause nodules in distal limbs. 9.Lung damage The incidence of lung damage is low, about 5%~10%, but most of the disease is serious. Pulmonary vascular involvement can have pulmonary aneurysm formation, rupture of the aneurysm can form pulmonary vascular – bronchial fistula, resulting in intrapulmonary hemorrhage; pulmonary vein thrombosis can lead to pulmonary infarction; alveolar peripapillary inflammation can make the endothelial hyperplasia and fibrosis to affect the function of air exchange. When the lungs are involved, patients have cough, hemoptysis, chest pain, dyspnea and so on. Coughing up a large amount of blood can lead to death. 10.Other Kidney damage is rare, there may be intermittent or persistent proteinuria or hematuria, renal hypertension, renal pathology may have IgA glomerular proliferative lesions or amyloidosis. Cardiac involvement is less common and may include myocardial infarction, valvular lesions, conduction system involvement, and pericarditis. There may be ependymal thrombosis in the cardiac chambers, and in a few patients, the heart shows dilatation-like changes, constrictive pericarditis-like manifestations, and cardiac lesions are associated with local vasculitis. The incidence of epididymitis is about 4%~10%, which is more specific. Acute onset, manifested as single or bilateral epididymis swelling pain and pressure, 1~2 weeks can be relieved, easy to recur. Pregnancy may aggravate the disease in most patients, and remission of uveitis has also been reported. There can be intrauterine fetal growth retardation, and most of the disease worsens after delivery. Nearly 10% of patients with fibromyalgia syndrome-like manifestations, more common in women. Diagnostic points] 1, the clinical manifestations of the disease course of the doctor observed and recorded recurrent oral ulcers, ophthalmia, genital ulcers and characteristic skin damage, in addition to the appearance of macrovascular or neurological damage is highly suggestive of the diagnosis of leukoencephalomalacia. 2.Laboratory examination There is no specific laboratory abnormality in this disease. In the active stage, there may be rapid blood sedimentation, elevated C-reactive protein; some patients are positive for cryoglobulin and platelet agglutination; the positive rate of HLA-B51 ranges from 57% to 88%, which is related to eye and digestive tract lesions. 3, Pathergy test (Pathergy test) with a sterile 20-gauge needle in the middle of the forearm flexion surface diagonal stabbing about 0.5cm along the longitudinal direction with a slight twist and then exit, 24 ~ 48 hours after the local appearance of folliculitis-like red spots or pustular herpes-like changes in the diameter of > 2mm is positive. This test has high specificity and correlates with disease activity, with a positive rate of about 60%~78%. Similar lesions after venipuncture or skin trauma are of equal value. 4.Special examination Neuroleukodystrophy is often characterized by increased cerebrospinal fluid pressure and mildly elevated white blood cell count. Brain CT and magnetic resonance (MRI) examination is helpful for brain, brainstem and spinal cord lesions. The sensitivity of MRI examination in the acute stage is as high as 96.5%, and it can find increased signals in the brainstem, paraventricular white matter and basal ganglia. MRI in the chronic stage should be noted to distinguish from multiple sclerosis.MRI can be used for the diagnosis of neuroleukodystrophy and the follow-up observation of the treatment effect. Barium gastrointestinal imaging and endoscopy, angiography, color Doppler can help to diagnose the site and scope of the lesion. Lung radiographs may show diffuse exudate or round nodular shadows of varying sizes unilaterally or bilaterally, and blurred shadows of increased density around the pulmonary hilum in the case of pulmonary embolism. High-resolution CT or pulmonary angiography and isotope lung ventilation/perfusion scanning are helpful in the diagnosis of lung lesions. 5. Diagnostic criteria There are no specific serologic and pathologic features in this disease, and the diagnosis is mainly based on clinical symptoms, so attention should be paid to detailed history taking and typical clinical manifestations. At present, the classification criteria formulated by the International Study Group on Leukosis in 1989 (see the attached table) are more often used. International Classification Criteria for Leukosis 1. Recurrent oral ulcers: three recurrent episodes within one year. Observed by the doctor or complained by the patient with aphthous ulcers. 2. Recurrent vulvar ulcers: Aphthous ulcers or scars on the vulva as observed by a physician or complained by the patient. 3. Eye lesions: anterior and/or posterior uveitis, presence of cells in the vitreous on slit lamp examination or retinal vasculitis observed by an ophthalmologist. 4. Skin lesions: erythema nodosum, pseudofolliculitis, or papular pustules observed by a physician or reported by the patient; or acne-like nodules in a nonpubertal patient not taking glucocorticoids. 5. Positive pinprick test: the results are seen by a physician 24-48 hours after the test. A diagnosis of the disease is made if there are recurrent mouth ulcers with 2 or more of the other 4 items, but other diseases need to be excluded. Other symptoms that are strongly associated with the disease and favor the diagnosis are: arthralgia or arthritis, subcutaneous embolic phlebitis, deep venous embolism, arterial embolism and/or aneurysm, central neuropathy, peptic ulcers, epididymitis, and family history. When applying the criteria, note that: not all patients with leukoaraiosis meet the criteria of the International Study Group; attention to vascular and neurologic lesions should be part of the evaluation of the disease; and multiple manifestations of the patient’s disease can occur over a period of several years, which should be documented by a physician as a basis for diagnosis. 6. Differential diagnosis The disease is easily misdiagnosed as a disease of other systems when symptoms of one system are prominent. If joint symptoms are the main manifestation of the disease, it should be differentiated from rheumatoid arthritis, Reiter’s syndrome and ankylosing spondylitis. Skin and mucous membrane damage should be differentiated from erythema multiforme, erythema nodosum, syphilis, Sweet’s disease, Stevens-Johnson’s syndrome, acne vulgaris, herpes simplex infections, tropical mouth sores, systemic lupus erythematosus, cyclic granulocytopenia, AIDS (AIDS), and other diseases. granulocytopenia, and AIDS; gastrointestinal involvement should be differentiated from restrictive enteritis (Crohn’s disease) and ulcerative colitis. Neurological damage should be distinguished from infectious and allergic cerebrospinal meningitis, cerebrospinal tumors, multiple sclerosis, and psychosis; epididymitis should be distinguished from epididymal tuberculosis. Treatment options and principles] There is no recognized effective cure for this disease. A variety of drugs are effective, but most of them are prone to relapse after stopping drugs. The purpose of treatment is to control the existing symptoms, prevent and control the damage of important organs, slow down the progress of the disease. 1, general treatment Acute active period, should be bed rest. During the interictal period, attention should be paid to the prevention of recurrence. Such as controlling mouth and pharyngeal infections, avoiding stimulating food. Accompanying infected people can be treated accordingly. 2.Local treatment Oral ulcers can be localized with glucocorticoid cream, ice boron powder, tin-like powder, etc. Genital ulcers can be washed with 1:5000 potassium permanganate and antibiotic ointment; ocular conjunctivitis and keratitis can be applied with corticosteroid ophthalmic ointment or eye drops; ocular uveitis should be applied with pupil-dilating agent in order to prevent the post-inflammatory adhesions; in severe ophthalmositis, adrenal corticotropic hormone can be injected in the subglobe-conjunctivitis. (1) Non-steroidal anti-inflammatory drugs: anti-inflammatory and analgesic effects. For the relief of fever, skin nodules erythema, genital ulcer pain and arthritis symptoms have a certain efficacy, commonly used drugs are ibuprofen 0.4-0.6g 3/d; naproxen, 0.2-0.4g 2/d; diclofenac sodium, 25mg 3/d, etc., or other non-steroidal drugs and COX-2 selective inhibitors (see rheumatoid arthritis treatment). (2) Colchicine: can inhibit neutrophil chemotaxis, and has some therapeutic effects on arthropathy, erythema nodosum, oral and genital ulcers, and uveitis, 0.5 mg 3/d. Attention should be paid to adverse effects such as hepatic and renal damage and granulocytopenia. (3) Thalidomide: used for the treatment of severe oral and genital ulcers. It is recommended to start with a small dose and gradually increase it to 50mg 3/d. It is contraindicated in pregnant women to avoid fetal malformation (see Ankylosing spondylitis medication), and it has the side effect of causing neuraxial degeneration. (4) Glucocorticoids: effective in controlling acute symptoms, commonly used for prednisone 40~60mg/d. Serious patients such as severe ophthalmitis, central nervous system lesions, severe vasculitis patients can be considered to use intravenous application of high-dose methylprednisolone shock, 1,000mg/d, 3~5 days for a course of treatment, and the combination of immunosuppressive drugs is more effective. Regular application of glucocorticoids has adverse effects (see Systemic Lupus Erythematosus Medications). (5) Immunosuppressants: these drugs should be used when important organs are damaged. They are often used in combination with adrenocorticotropic hormones. The side effects of these drugs are large, and close monitoring should be paid attention to the time of drug use. ①Nitrogen mustard phenylbutyrate (Chlorambucil, CB1348): used in the treatment of retinal, central nervous system and vascular lesions. It should be used at 2mg 3/d for several months until the disease is stabilized and then tapered to a low maintenance dose. Discontinuation of the drug can be considered after six months of complete remission. However, eye damage should be considered for more than 2~3 years to avoid recurrence. During the use of the drug, regular ophthalmologic consultation and examination should be conducted. Side effects include secondary infections, menopause or sperm reduction and azoospermia with long-term use. ② Azathioprine: the effect is worse than azathioprine phenylbutyrate. The dosage is 2~2.5mg/kg/d. It can inhibit oral and ocular lesions and arthritis, but it is easy to relapse after stopping the drug. It can be used in combination with other immunosuppressants. During the application period, blood routine and liver function should be checked regularly. Methotrexate: 7.5~15mg per week, taken orally or by injection. It is used to treat lesions of the nervous system, skin and mucous membranes, and can be taken in small doses for a long time. Adverse reactions include bone marrow suppression, liver damage and gastrointestinal symptoms. Regular check of blood routine and liver function should be performed. ④ Cyclophosphamide (Cyclophosphamide): in acute central nervous system damage or pulmonary vasculitis, ophthalmia, combined with prednisone, can be taken orally or high-dose intravenous shock treatment (each dosage of 0.5 ~ 1.0/O body surface area, every 3 ~ 4 weeks). Patients should be instructed to drink large amounts of water to avoid hemorrhagic cystitis. In addition, there may be gastrointestinal reactions and leukopenia (see Systemic Lupus Erythematosus Medications). ⑤ Cyclosporine (Cyclosporine): It is more effective in ocular leukoaraiosis where colchicine or other immunosuppressive agents are ineffective. The dose is 3~5mg/kg/d. When applying, pay attention to monitoring blood pressure and liver and kidney function to avoid adverse reactions. (6) Liuzasulfapyridine: 3~4g/d, can be used for those with intestinal leukoaraiosis or arthritis. (6) Others ①α interferon: it is effective in the treatment of oral damage, skin disease and joint symptoms, and can also be used in the acute phase treatment of eye lesions. ② TNF monoclonal antibody (Infliximab) has been reported for the treatment of recurrent uveitis efficacy is certain, but still need further clinical observation. (iii) Tretinoin preparations have positive efficacy in oral ulcers, subcutaneous nodules, arthropathy, and ophthalmia. The efficacy on intestinal symptoms is poor. ④ Anticoagulants (aspirin, Pansentin) and fibrin therapy (urokinase, streptokinase) can also be used in the treatment of thrombotic disorders, but they should not be stopped abruptly to avoid rebound. ⑤ If the patient has tuberculosis or has a history of tuberculosis, and the PPD subcutaneous test is strongly positive (5Iu with blisters), anti-tuberculosis treatment (triple) can be tried for at least three months and the efficacy can be observed. 4.Surgery Surgical treatment is feasible when severe intestinal leukoencephalopathy is complicated by intestinal perforation, but the recurrence rate of intestinal leukoencephalopathy after surgery can be as high as 50%. Recurrence has nothing to do with surgical method and primary site, so the choice of surgery should be careful. Vascular lesions can also form aneurysms again at the postoperative anastomosis after surgery, so generally do not advocate surgical treatment, the use of interventional therapy can reduce the complications of surgery. Eye blindness with persistent pain can be removed surgically. After surgery, immunosuppressive therapy should be continued to reduce recurrence.