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Behcet Syndrome
Background: Behçet syndrome is a multisystem disease probably first described by Hippocrates in the 5th century. The syndrome carries the name of the Turkish dermatologist Hulusi Behçet, who, in 1937, described a syndrome of recurrent aphthous ulcers, genital ulcerations, and uveitis leading to blindness. Although the cause of the disease is still unknown, it has become recognized as a multisystemic inflammatory disease.

Pathophysiology: Behçet syndrome is characterized by recurrent aphthous ulcers, genital ulcers, and uveitis or retinal vasculitis. Other manifestations of the disease include skin lesions; arthritis; gastrointestinal lesions; central nervous system (CNS) involvement; and vascular lesions, including aneurysms and thrombosis. In Behçet syndrome, the basic lesion is vasculitis. Biopsies have shown vasculitis near lesions of Behçet syndrome, including the oral and genital ulcers and lesions of the CNS and in the eyes; large vessels are affected by a vasculitis of the vasa vasorum. Vascular injuries may be superimposed on the hypercoagulability seen in some patients.

Neutrophilic hyperfunction is seen in patients with Behçet syndrome with neutrophilic infiltration of skin at the site of a prick with a sterile needle (the pathergy test). Lymphocyte function also has been reported as abnormal, with a clonal expansion of autoreactive T-cells.

Frequency:

  • In the US: Figures available from Olmstead County, Minnesota reveal prevalence in this community to be 5 per 100,000 persons. Other estimates of prevalence vary from 0.12 to 0.33 per 100,000.
  • Internationally: Frequency data for Behçet syndrome should be considered suspect due to problems with case ascertainment. This problem is inherent in any disease where there is no specific diagnostic test, but only a set of clinical criteria for diagnosis. Behçet syndrome is thought to be more common along the ancient Silk Road, extending from Asia to the Mediterranean. Estimates from Turkey vary from 80 to 370 per 100,000, while prevalence estimates from Japan, Korea, China, and the Middle East vary from 13 to 20 per 100,000. In northern Spain, prevalence has been reported as 0.66 per 100,000, while estimates from Germany are 2.26 per 100,000.

Mortality/Morbidity:

  • Ocular: Blindness is a serious manifestation of Behcet syndrome, with 60-80% of patients having uveitis. Retinal arterial and venous lesions are prognostic indicators for blindness. In Middle Eastern populations, mean time from onset of disease to blindness is 3-4 years, if not treated, or if treated only with corticosteroids.
  • CNS: Neurological involvement is one of the most serious manifestations of Behçet syndrome, occurring in 10-30% of patients and carrying a poor prognosis. Manifestations include meningitis or meningoencephalitis; psychiatric symptoms, including personality changes; neurological deficits, including hemiparesis; and brainstem symptoms. Neurological deficits may be progressive, with 30% of Behcet syndrome patients with neurologic manifestations eventually developing dementia.
  • Vascular: Large venous or arterial lesions occur in 7-40% of patients. Venous involvement typically includes superficial thrombophlebitis or deep venous thrombosis. Arterial manifestations may present as thrombosis or aneurysm formation, with possible fatal rupture.

Race: Behçet syndrome is felt to be more common in Turkish, Asian, and Middle Eastern populations, although it may be that the severity of disease is increased in these populations, with better case ascertainment as a result. An increased incidence of skin pathergy and HLA-B5 antigen is seen in Middle Eastern and Asian patients, compared to North American or northern European patients.

Sex: In Japan and Korea, Behçet syndrome is more common in females, with a male-to-female ratio of 1:2, but is more common in males in the Middle East, with a ratio of 2:1. In the literature, estimates of male-to-female ratios range from 11:1 to 0.2:1. Despite the variability of the reported sex ratios, it is agreed that the disease runs a more severe course in males.

Age: Onset typically is in patients in their late 20s or early 30s. Onset during the childhood years, is well recognized, but Behcet syndrome rarely occurs before school age. Mean age of onset for pediatric patients in a large Turkish series was 11.7 years.

History: Two sets of criteria are commonly used for diagnosis of Behçet syndrome: an international criteria for Behçet syndrome, derived in 1990, and the O'Duffy criteria. Both sets of criteria may be too stringent for application in children who have lower risk for oral or genital ulcerations from other cause.

  • The international criteria include recurrent oral ulcerations, plus 2 of the following:
      • Recurrent genital ulcerations
      • Eye lesions
        • Anterior uveitis
        • Posterior uveitis
      • Cells in the vitreous
      • Retinal vasculitis
      • Skin lesions
        • Erythema nodosum
        • Pseudo folliculitis
        • Papulopustular lesions
        • Acneiform nodules (in a postadolescent patient not taking corticosteroids)
      • Positive pathergy test
    • The O'Duffy criteria requires that in addition to recurrent aphthous ulcerations, any two of following be present:
      • Genital ulcers
         
      • Uveitis
         
      • Cutaneous pustular vasculitis
         
      • Synovitis
         
      • Meningoencephalitis
         
      • In addition, one must exclude inflammatory bowel disease, systemic lupus erythematosus (SLE), Reiter's syndrome, and herpetic infections.
    • Oral ulceration, the hallmark of this disease, is usually the initial clinical symptom, and can precede other manifestations by years. Ulcers are typically painful, appear in crops, and are nonscarring. For diagnostic purposes, expect at least 3 episodes in a 12-month period. In one study of pediatric Behçet syndrome, the average time interval between the initial oral ulceration and the second manifestation was 8.8 years.
    • Genital ulcers appear in the vulva and vagina in females and scrotum and penis in men. Ulcers are painful, recurring, and scarring.
    • Ocular manifestations can be asymptomatic initially, or they may present quite dramatically as hypopyon uveitis. Patients may complain of blurred vision, eye pain, photophobia, increased lacrimation, and erythematous conjunctiva.
    • Skin manifestations are nonspecific and include erythema nodosum, folliculitis, and pustular rash.
    • Arthralgias and arthritis can occur in small or large joints. Sacroiliitis has been described in HLA-B27 positive patients.
    • Gastrointestinal complaints are common and include abdominal pain, diarrhea, and melena. Perforation may occur.
    • CNS involvement may occur in up to 25% of children, and is the most severe manifestation of the disease. Meningoencephalitis presents as headache and stiff neck; focal neurological abnormalities also can be seen. Neuropsychiatric symptoms include hallucinations and personality changes; Other features that have been described include brainstem lesions; pseudotumor cerebri; cranial nerve palsies; and pyramidal, extrapyramidal, and cerebellar symptoms.
    • Vascular involvement includes venous and arterial thrombosis and vascular aneurysm formation. Intracranial venous occlusion may present with headache and visual blurring. Rupture of a vascular aneurysm may be fatal. Well-known syndromes of large venous occlusions, such as Budd-Chiari syndrome or superior vena-caval syndrome, may occur.
    • Pulmonary manifestations include pulmonary vasculitis and pulmonary arterial aneurysm formation, which may present with hemoptysis, dyspnea, chest pain, or cough.

    Physical: Physical findings will vary, reflecting the disease manifestations of a particular patient.

    • Oral ulcerations: Ulcers are typically 2-15 mm in diameter, with a necrotic center and surrounding red rim. A white or yellow pseudomembrane covers the surface of the ulcer. The ulcers are typically painful; nonscarring; and found on the lips, buccal mucosa, tongue, tonsils, and larynx. Most last 7-14 days and occur in crops.
    • Genital ulcerations: These typically occur less often than the oral ulcerations. The ulcers occur on the scrotum and vulva, are painful, and heal with scarring, especially on the scrotum. Genital ulcerations tend to be deeper and larger than the oral lesions. Females can have asymptomatic ulcers, especially in the vagina.
    • Ocular manifestations: Uveitis can occur in both the anterior and posterior chambers of the eye. Frank pus (hypopyon) may be seen in the anterior chamber. Retinal vasculitis is the most serious ocular finding. Vaso-occlusive lesions of the posterior chamber may cause a progressive decreased visual acuity. A slit lamp exam is necessary for diagnosis of uveitis, and fluorescein angiography is useful to identify retinal lesions.
    • Skin manifestations: Erythema nodosum lesions typically occur on the extremities, especially the lower extremities, but they also can be seen on the face, neck, and buttocks. The lesions are painful, resolving spontaneously, although some ulcerate. Lesions may leave a hyperpigmented area on the skin. A folliculitis-like rash, resembling acne vulgaris, appears on the face, neck, chest, back, and hairline of patients. Some lesions will become more pustular. Twenty-four to forty-eight hours after a sterile needle prick, patients will develop erythema with a nodule or pustule at the prick site. This pathergy response commonly is seen in patients from Asia and the Middle East and is uncommon in northern European and North American patients.
    • Monoarthritis or polyarthritis occurs in at least 50% of patients. Knees are the most commonly affected joints, followed by wrists, ankles, and elbows. The arthritis typically is nonerosive.
    • Besides the oral mucosa, ulcerative lesions may occur anywhere in the gastrointestinal tract. Most commonly, ulcers occur in the ileocecal region. Other involved areas include the transverse and ascending colon and esophagus. Anticoagulation is controversial in patients with Behçet syndrome because of the risk of bleeding from one of these ulcers.
    • CNS involvement occurs in up to 25% of patients and may be the most serious manifestation of disease. The CNS lesions may have exacerbations and remissions. In some patients irreversible dementia ultimately results. Findings may include meningitis, encephalitis, focal neurological deficits, and psychiatric symptoms.
    • Vascular involvement
      • Venous involvement includes migratory superficial thrombophlebitis of the skin and deep venous thrombosis. Occlusion of major veins may cause bleeding, infarction, organ failure, or restriction of arm and leg movement. Up to 20% of patients with occlusive venous disease will be anticardiolipin antibody positive. Intracranial venous occlusion may present with headache and visual blurring. With venous occlusion, one may see formation of collateral circulation.
      • Arteritis may involve the aorta or its branches and lead to aneurysm formation. Rupture of aneurysms may be fatal. Pulmonary artery involvement may result in aneurysm formation with pulmonary artery to bronchus fistula formation and resultant hemoptysis. Aneurysm formation carries a worse prognosis than occlusive disease.
      • Cardiac valves may grow vegetations with subsequent emboli. Clinically, these lesions are similar to bacterial endocarditis, but cultures are negative and round cell infiltration most typically is seen on histology.
      • Nephrotic syndrome and kidney amyloidosis have rarely been described in patients with Behcet syndrome.
    • Myositis has been described in pediatric Behcet syndrome.

    Causes: The etiology of Behçet syndrome is unknown. It is felt that Behçet syndrome is caused by a combination of hereditary and environmental factors. The HLA-B51 allele (one of the split antigens of B5) commonly is found in patients from Asia and the Middle East, yet rarely found in northern European and North American patients. It has been suggested that infections may play a pathogenic role, with patients who have Behçet syndrome having a higher incidence of antibodies to herpes simplex virus, hepatitis C virus, and parvovirus B19. Streptococcal antigens also have been implicated; a trial of prophylactic penicillin treatment decreased the number of acute arthritis episodes in patients with Behçet syndrome.

    • Patients who have a parent with Behçet syndrome have disease onset at a younger age (genetic anticipation). In addition, pediatric patients are more likely to have a family history of Behçet syndrome, compared to patients with disease onset as an adult.

    Other Problems to be Considered:

    Primary anti-phospholipid antibody syndrome
    Multiple sclerosis
    Stevens-Johnson syndrome

    • Lab Studies:

    • No specific laboratory test is diagnostic of Behçet syndrome.
      • Serum complement levels are normal, except for just prior to eye or mucous membrane involvement, at which time they may be decreased.
      • Sedimentation rate or C-reactive protein may be elevated.
      • HLA-B51 may be present in patients of Asian, Mexican, or Middle Eastern descent.
      • Anticardiolipin antibodies are present in up to 30% of patients.
    • Systemic lupus erythematosus and other vasculitic syndromes must be ruled out (with negative antinuclear antibodies and negative antineutrophilic cytoplasmic antibodies).
    • In patients with CNS findings, there may be cerebral spinal fluid pleocytosis.
    • In addition to thrombosis associated with antiphospholipid antibodies, there have been reports of thombosis in Behçet syndrome associated with Factor V Leiden mutations, and with prothrombin G20210A mutations.

    Imaging Studies:

    • For patients with CNS involvement, brain MRI and/or computed tomography (CT) for visualization of the neurological lesions is often helpful. Focal lesions may be seen anywhere in the CNS on the MRI, appearing as high signal on the T2 weighted images and low signal on the T1 weighted images. Enlargement of ventricles or subarachnoid spaces may be seen. However, the MRI of the brain may be normal even in the presence of neurological involvement. Neuropsychological testing may be abnormal prior to any detectable lesions on neuro-imaging.
    • Angiography: Angiography will show areas of aneurysm formation and thrombosis.
    • Echocardiogram: Consider an echocardiogram in patients with murmurs, as it is useful for diagnosing the valve vegetations seen in Behçet syndrome.

    Other Tests:

    • Endoscopy of the gastrointestinal (GI) tract is useful for detecting gastrointestinal ulcerations.
    • A thorough eye examination by an experienced ophthalmologist is important. Consider fluorescein angiography. Follow-up visits with an ophthalmologist should be scheduled every 6-12 months.
    • Neuropsychological testing may be useful with CNS involvement, revealing memory impairment or personality changes, and can be useful in following neuropsychological status.

    Histologic Findings: Behçet syndrome is diagnosed clinically, not by means of tissue evaluation. However, round cell infiltration may be found in cardiac valve lesions. Biopsy of the buccal and genital ulcers reveal lymphocytic and plasma cell invasion in the prickle cell layer of the epidermis. Dermal vessels are infiltrated with lymphocytes and plasma cells with immune deposits of immunoglobulin M (IgM) and C3. Occasionally, necrotizing vasculitis is seen.

    Medical Care: Evaluation and treatment need to be tailored to each patient's clinical manifestations. Corticosteroids are considered palliative; they are useful in controlling acute manifestations, but progression of CNS and ocular disease may occur in patients treated with corticosteroids alone. Decreasing morbidity and mortality is the goal of treatment for children with Behçet syndrome.

    Surgical Care: Surgical resection of aneurysms with graft placement should be considered if feasible because of the high risk of aneurysmal rupture.

    Consultations: A rheumatologist should be consulted for all Behçet syndrome patients. For children, a pediatric rheumatologist is preferable. Consider other consultations depending on patient signs and symptoms.

    • Ophthalmology: All patients should have regular eye exams by an ophthalmologist experienced with vasculitis.
    • Neurology consultation should be considered for patients with CNS complaints.
    • A gastroenterology consultation is appropriate for evaluation and management of abdominal symptoms.
    • Vascular surgery consultation is important for patients with aneurysm formation.

    Diet: No specific dietary recommendations are needed for patients with Behçet syndrome. Anyone on long-term corticosteroid use should avoid excessive weight gain and should consider a low-salt, low-fat diet.

    Activity: Restriction of activity should be tailored to a patient's clinical manifestations.

    Choice of medications will depend on a patient's clinical manifestations. Ocular, CNS, and large vessel involvement is given priority in terms of treatment. Close communication between subspecialists is important for patient care. Corticosteroids have a suppressive effect on most manifestations of Behçet syndrome, but they do not prevent dementia or blindness. Immunosuppressive therapies appear to be effective in the long term.
    Drug Category: Anti-gout -- This medication is useful in decreasing frequency of mucosal ulcerations, the skin findings of pseudofolliculitis, and erythema nodosum, and can be useful in the management of uveitis and retinal vasculitis.

    Drug Name
         		 Colchicine (Acetycol, Colsalide) -- Mechanism of action is unknown, but may have to do with decreased motility of leukocytes. First line therapy for oral ulcerations, ocular manifestations, and skin lesions.
    Adult Dose 0.5-1.5 mg/d PO titrate up to maximal tolerated dose
    Pediatric Dose <5 years: 0.5 mg/d
    >5 years: 0.5-1.5 mg/d
    titrate up to maximal tolerated dose
    Contraindications Documented hypersensitivity; serious renal, GI, hepatic, or cardiac disorders; blood dyscrasias
    Interactions Decreased vitamin B12 absorption; increased toxicity of sympathomimetic agents; enhancement of CNS depressants
    Pregnancy X - Contraindicated in pregnancy
    Precautions Necessary to monitor CBC and renal function tests; high incidence of GI side effects (eg, nausea, vomiting, diarrhea, abdominal pain); may limit possible dosage

    Drug Category: Corticosteroids -- Decrease acute inflammatory manifestations of Behçet syndrome.

    Drug Name
         		 Triamcinolone acetonide ointment (Aristocort, Flutex, Kenalog) -- Topical treatment is useful to decrease the pain and inflammation of oral ulcers.
    Adult Dose Apply sparingly to affected area tid
    Pediatric Dose Apply sparingly to affected area tid
    Contraindications Documented hypersensitivity; systemic fungal infections; serious infections
    Interactions None reported
    Pregnancy C - Safety for use during pregnancy has not been established.
    Precautions Do not use in decreased skin circulation; prolonged use, applications over large areas, and use of potent steroids and occlusive dressings may result in systemic absorption; systemic absorption may cause Cushing's syndrome, reversible HPA axis suppression, hyperglycemia and glycosuria
    Drug Name
         		 Betamethasone ointment (Alphatrex, Diprolene, Maxivate) -- Useful to decrease the pain and inflammation of genital ulcers.
    Adult Dose Apply sparingly to affected area tid
    Pediatric Dose Apply sparingly to affected area tid
    Contraindications Documented hypersensitivity; systemic fungal infections; serious infections
    Interactions None reported
    Pregnancy C - Safety for use during pregnancy has not been established.
    Precautions Do not use in skin with decreased circulation; can cause atrophy of groin, face, and axillae; may cause striae distensae, rosacea-like eruption; may increase skin fragility; rarely may suppress HPA axis; if infection develops and is not responsive to antibiotic treatment, discontinue until infection is under control
    Drug Name
         		 Dexamethasone injectable (Decadron) -- Indicated for retinal vasculitis, injected below the Tenon capsule for an ocular attack.
    Adult Dose 1-1.5 mg intraocular injection
    Pediatric Dose 0.5-1.5 mg intraocular injection
    Contraindications Documented hypersensitivity; systemic fungal infections
    Pregnancy C - Safety for use during pregnancy has not been established.
    Precautions Local irritation
    Drug Name
         		 Prednisone (Deltasone, Orasone, Sterapred) -- Low-dose, second-line therapy for erythema nodosum, anterior uveitis, retinal vasculitis, and arthritis. High-dose, first-line therapy for GI lesions, acute meningoencephalitis, chronic progressive CNS lesions, and arthritis. Second-line treatment for retinal vasculitis and venous thrombosis.
    Adult Dose Low dose: 5-20 mg/d PO
    High dose: 20-100 mg/d PO
    Pediatric Dose Low dose: 0.05-.5 mg/kg/d PO
    High dose: up to 2 mg/kg/d PO
    Contraindications Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or
    tubercular skin infections; GI disease
    Interactions Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin, may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
    Pregnancy B - Usually safe but benefits must outweigh the risks.
    Precautions Gradual tapering of dose required; suppression of linear growth in children with high doses; increased risk of osteoporosis; possible reversible HPA axis suppression, Cushing's syndrome, hyperglycemia, and glucosuria
    Drug Name
         		 Methylprednisolone (Medrol, Solu-Medrol) -- Used as first-line therapy for acute meningoencephalitis, chronic progressive CNS lesions, and arteritis. Alternate therapy for GI lesions and venous thrombosis.
    Adult Dose 1000 mg/d IV for 3 d; weekly pulses acutely also possible
    Pediatric Dose 30 mg/kg/d IV up to 1000 mg; for 3 d; and/or weekly pulses acutely
    Contraindications Documented hypersensitivity; caution with any active infection; serious infections, except septic shock or tuberculous meningitis; septic fungal infections, varicella; administration of live virus vaccines
    Interactions Coadministration with digoxin, may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics
    Pregnancy C - Safety for use during pregnancy has not been established.
    Precautions Gradual tapering of dose required; suppression of linear growth in children with high doses; increased risk of osteoporosis; possible reversible HPA axis suppression, Cushing's syndrome, hyperglycemia, and glucosuria

    Drug Category: Cytotoxic agents -- Used for the more serious long-term effects of Behcet syndrome; eye, CNS involvement, severe vasculitis.

    Drug Name Azathioprine (Imuran) -- Used as alternate therapy for retinal vasculitis, arthritis, chronic progressive CNS lesions, arteritis, and venous thrombosis.
    Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.
    Adult Dose 100-150 mg/d PO
    Pediatric Dose 1-3 mg/kg/d PO
    Contraindications Documented hypersensitivity; pregnancy; lactation, low levels of serum thiopurine methyl transferase (TPMT)
    Interactions Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
    Pregnancy D - Unsafe in pregnancy
    Precautions Chronic immunosuppression increases the risk of neoplasia; mutagenic potential for both men and women; caution with liver disease and renal impairment; check TPMT level prior to therapy and follow liver, renal, and hematologic function; pancreatitis rarely associated
    Drug Name
         		 Chlorambucil (Leukeran) -- Used as alternate therapy for retinal vasculitis, arthritis, chronic progressive CNS lesions, arteritis, and venous thrombosis.
    Alkylates and cross-links strands of DNA inhibiting DNA replication and RNA transcription.
    Adult Dose 5 mg/d PO; adjust dose depending on blood counts
    Pediatric Dose 0.1-0.2 mg/kg/d PO; adjust dose depending on blood counts
    Contraindications Documented hypersensitivity; pregnancy; lactation
    Interactions None reported
    Pregnancy D - Unsafe in pregnancy
    Precautions Possible severe suppression of bone marrow function; affects human fertility; carcinogenic in humans; possible association of secondary acute myelogenous leukemia with chronic therapy; monitor hematologic parameters weekly while on medication
    Drug Name
         		 Cyclophosphamide (Cytoxan, Neosar) -- Used as alternate therapy for retinal vasculitis, arthritis, chronic progressive CNS lesions, arteritis, and venous thrombosis.
    A cell cycle phase nonspecific antineoplastic agent and immunosuppressant. A pro-drug that requires activation by the cytochrome P-450 system in order to be cytotoxic.
    Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
    Adult Dose 50-100 mg/d PO
    700-1000 mg or 1 g/m2 IV monthly
    Pediatric Dose 50-100 mg/m2/d PO
    500-1000 mg/m2/dose IV monthly; up to 1000 mg total dose
    Contraindications Documented hypersensitivity; severely depressed bone marrow function
    Interactions Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects. Cyclophosphamide may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones. Chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulant; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
    Pregnancy D - Unsafe in pregnancy
    Precautions Possible dose adjustment needed in hepatic or renal failure; caution with bone marrow depression; monitor post infusion CBC; chronic immunosuppression increases risk of neoplasia; possible reduction of risk of hemorrhagic cystitis with MESNA for infusion therapy; attention to adequate hydration with PO therapy; patient education to report any hematuria warranted
    Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis
    Drug Name
         		 Methotrexate (Folex PFS, Rheumatrex) -- An antimetabolite that interferes with the enzyme dihydrofolate reductase leading to depletion of DNA precursors and inhibition of DNA and purine synthesis particularly adenosine.
    Unknown mechanism of action in treatment of inflammatory reactions (although may involve adenosine receptors and cell-cell adhesion); may affect immune function. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust dose gradually to attain satisfactory response.
    Adult Dose 7.5 –15 mg/wk PO/SC
    Pediatric Dose 10 mg/m2/wk; may push dose as clinically indicated up to 30 mg/m2/wk (or 1 mg/kg)
    Contraindications Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency
    Interactions Oral aminoglycosides may decrease absorption and blood levels of concurrent oral methotrexate (MTX); charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX
    Use with caution with NSAIDs; indomethacin and phenylbutazone can increase MTX plasma levels; may decrease phenytoin serum levels
    Probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity of MTX; may increase plasma levels of thiopurines
    Pregnancy D - Unsafe in pregnancy
    Precautions Possible photosensitivity reaction; monitor for pulmonary disease; caution with peptic ulcer disease and preexisting bone marrow suppression; possible hepatotoxicity, fibrosis, cirrhosis, and bone marrow suppression
    Monitor CBCs monthly, and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg, dehydration); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems
    Discontinue if significant drop in blood counts; aspirin, NSAIDs, or low dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs including salicylates has not been tested)
    Drug Name
         		 Cyclosporine (Sandimmune, Neoral) -- First-line therapy for retinal vasculitis.
    Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft vs host disease for a variety of organs. For children and adults, base dosing on ideal body weight.
    Adult Dose 5 mg/kg
    Pediatric Dose 2-5 mg/kg/d PO divided bid or tid
    Contraindications Documented hypersensitivity; uncontrolled hypertension or malignancies
    Interactions Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin
    Pregnancy C - Safety for use during pregnancy has not been established.
    Precautions Possible CNS symptoms identical to those classically associated with Behcet syndrome in 20-30% of patients; possibility of neurological symptoms, with potentially irreversible CNS disability; possible infection and lymphoma development; adjustment of dose may be aided by monitoring of serum cyclosporin levels; nephrotoxic; possible hypertension; gradual decline in efficacy
    Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin and liver enzymes; reserve IV use only for those who cannot take PO

    Further Inpatient Care:

    • Patients may need to be admitted during acute flares for IV therapy or for diagnostic testing or surgical intervention.

    Further Outpatient Care:

    • Close follow-up care is warranted to monitor clinical status, including routine eye examinations.

    Transfer:

    • Transfer to a tertiary care center for diagnosis and intervention may be warranted, depending on the clinical symptomatology.

    Deterrence/Prevention:

    • No preventative measures are known for Behçet syndrome.

    Complications:

    • Complications include those caused by medications and the primary disease, and vary depending on clinical presentation and disease manifestations.

    Prognosis:

    • Prognosis depends on clinical manifestations. The worst prognoses are associated with retinal vasculitis, leading to blindness; vascular aneurysm formation, with possible rupture; and neuro-Behçet syndrome, which may lead to dementia despite appropriate aggressive treatment.

    Patient Education:

    • Patients need to be educated in disease manifestations, long-term prognosis, and medication side effects.

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