eMedicine Specialties > Ophthalmology > Unclassified Disorders
Behcet Disease: Treatment & Medication
Updated: Oct 12, 2007
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
- Treatment of the various manifestations of Behçet disease remains controversial because of the paucity of randomized, controlled trials and the absence of standardized outcome measures for this disease. For example, colchicine, which has historically been the drug of choice for the treatment of the various manifestations of Behçet disease, has been evaluated for its efficacy and safety in only one randomized, controlled trial. In this 2-year trial, colchicine was found to only decrease arthritis in male and female patients and to decrease genital ulcers and erythema nodosum in female patients.2
- The goals of therapy in Behçet disease are to suppress inflammation, to reduce the frequency and severity of recurrences, and to minimize involvement of the retina.
- To be effective, treatment must be started early. Extent of involvement and severity of disease determine the choice of medication. Treatment options include corticosteroids, cytotoxic agents, cyclosporine, and colchicine.
- Corticosteroids
- Systemic corticosteroids effectively suppress all phases of ocular involvement in Behçet disease.
- Although these drugs do not prevent visual deterioration, systemic corticosteroid therapy may still be helpful, especially when used in concurrence with other immunosuppressive agents.
- Prednisone may be used in a pulse mode to treat Behçet disease, with a 1-g bolus given intravenously over 1 hour and repeated once a day for 3 days. The pulse treatment is repeated as needed.
- In Japan, systemic corticosteroids are not used for ocular disease. This decision is based upon the findings of several retrospective studies that show long-term visual outcomes to be worse in patients who receive systemic corticosteroids compared to those who did not.
- Cytotoxic agents
- Chlorambucil, cyclophosphamide, and azathioprine are the cytotoxic agents used most commonly for the treatment of Behçet disease.
- Chlorambucil was the first cytotoxic drug to be used in the treatment of ocular Behçet disease. This slow-acting alkylating agent may be administered on an outpatient basis.
- Cyclophosphamide is an alkylating agent that is superior to corticosteroids in the control of inflammation in Behçet disease, but profound bone marrow toxicity limits its use. Since cyclophosphamide acts faster and is more toxic than chlorambucil, its use is reserved for very refractory cases.
- Azathioprine is a mercaptopurine derivative that is effective in the treatment of Behçet disease.
- All of these cytotoxic agents may produce variable degrees of bone marrow suppression and may affect reproductive organs resulting in azoospermia and amenorrhea.
- Cyclosporine
- Cyclosporine inhibits T-lymphocyte activation and consequently is safer than cytotoxic agents; however, renal complications may occur.
- Usual starting dose is 5 mg/kg per day. Cyclosporine does not appear to induce permanent immunosuppression; therefore, patients need continuous treatment for many years.
- A rebound phenomenon has been noted after withdrawal of cyclosporine therapy.
- These factors have limited the use of cyclosporine for the treatment of Behçet disease, but a study conducted in Japan found that a starting dose of 5 mg/kg per day effectively limited the frequency of ocular inflammatory attacks in 70% of patients with Behçet disease who previously had refractory disease.
- Colchicine
- Colchicine is a plant alkaloid that interferes with microtubule function, which results in dysfunction of neutrophils.
- Colchicine may be used with other drugs and may enable the disease to be controlled using lower doses of immunosuppressants. The optimum dosage of colchicine is 0.5-1 mg/d.
- In Japan, colchicine is considered the drug of choice because of its few adverse effects and because of the presumed poor long-term prognosis of systemic corticosteroids.
- When colchicine fails to limit recurrences, treatment is switched to or combined with cyclosporine.
- It appears that the best results may be obtained using a combination of drugs, such as corticosteroids with either cytotoxic agents or cyclosporine.
- Overall, no safe and conclusive treatment exists for patients with Behçet disease. The treatment regimen needs to be tailored to the severity and extent of disease in each individual case.
- The goal of therapy is to suppress inflammation, to prevent sequelae, and to minimize the systemic adverse effects of treatment.
- Newer therapies have been advocated; see Media file 1 for a complete review.1
- Biological therapies
- Interferons
- Interferons (INFs) are a large family of glycoproteins that possess antiviral, antitumor, and immunomodulatory properties. The rationale for their use in Behçet disease is founded, firstly, on the putative association between the disease and viral infections and, secondly, on their biologic effects, including the ability to improve the activity of natural killer cells and to inhibit gamma delta T cells.1
- The most impressive results have been achieved for severe and/or refractory ocular manifestations. Patients with mucocutaneous and articular manifestations also benefit from interferon alpha (IFN-alpha), but there are fewer complete remissions, and relapses often occur after discontinuation. Intermediate-to-high IFN-alpha doses are more effective than low-dose regimens, and long-term remissions are associated with higher IFN-alpha doses but not with longer treatment duration. Adverse effects are frequent but dose dependent and not severe. They are the same as those reported for IFN-alpha in the treatment of other disorders, such as chronic hepatitis B or C, or hematological diseases, such as chronic myelogenous leukemia or non-Hodgkin lymphoma.1
- TNF-alpha inhibitors
- The rationale for anti-TNF use in Behçet disease is founded on the strong implication of TNF-alpha in the pathogenesis of this disease. It is well known that Behçet disease is mediated by a variety of cytokines, including TNF-alpha released from Th1 lymphocytes. Patients with active disease demonstrate increased numbers of monocytes and T lymphocytes expressing gamma/delta receptors that overproduce TNF-alpha. Patients also show increased levels of circulating TNF-alpha and soluble receptors, and high TNF-alpha levels are observed in the aqueous humor from patients with uveitis associated with Behçet disease.1
- Both infliximab (a chimeric monoclonal antibody to TNF-alpha) and etanercept (a dimeric, soluble p75 TNF receptor) have been shown to be effective in the treatment of various inflammatory disorders.
- Results of therapeutic studies suggest that this drug is highly effective in inducing short-term remission of virtually all manifestations of the disease, including sight-threatening panuveitis. In cases of ocular inflammation, remission was observed in some patients within 24 hours, and marked improvement of visual acuity was observed in other patients by 7 days. Infliximab was usually administered in doses of 3–5 mg/kg with continuous treatment every 2 months for as long as 2 years in some patients. Complete remission has been maintained with a reduction in concomitant immunosuppressive therapy. Continuous therapy has been reported in most studies, but a few patients have remained in remission for up to 12 months after treatment. Data that continue to accumulate strongly suggest that infliximab and etanercept are effective and safe in the treatment of Behçet disease. Whether infliximab is more effective than etanercept in the treatment of Behçet disease remains unclear.
- Both IFN and TNF blockers seem to be effective in the management of ocular and extraocular manifestations of Behçet disease. However, the data need to be further verified by randomized, controlled trials in larger numbers of patients with longer follow-up periods.1
- Other alternative therapeutic strategies
- Tolerizing agents
- Tolerance induction has primarily been used for the treatment of autoimmune uveitis, as it is known to be caused by lymphocytes that recognize and attack self-protein antigens within the eye. S-antigen (S-Ag) and interphotoreceptor retinoid binding protein (IRBP) are the best characterized self-antigens. Conventional therapeutic approaches suppress the activity of the leukocytes (anti-inflammatory) and lymphocytes (immunosuppressive) in an unspecific manner, leading to suppression of the entire immune system. New immunoregulatory approaches that suppress only the aberrant immune response to ocular antigens are under development. One of these approaches is mucosal tolerance, a mechanism of specific immune tolerance to soluble antigens applied via mucosal surfaces.1
- To date, various oral antigens have been applied to patients with uveitis. They have included IRBP, retinal S-Ag, retinal extracts, and a peptide from the sequence of associated HLA-B-antigens mimicking retinal S-Ag peptide.1
- Oral tolerance seems to be safe and effective in Behçet disease. Yet, clinical trials have been performed on a limited number of patients; therefore, these results have to be interpreted cautiously.1
- Immunoablation: Several case series have demonstrated the efficacy of autologous hematopoietic stem cell transplantation (HSCT) in inducing remission in patients with Behçet disease.1
Consultations
- Uveitis service if available
- Gastroenterology
- Rheumatology
- Neurology: Neuro-Behçet disease must be considered in the differential diagnosis of stroke in young adults, multiple sclerosis, movement disorders, intracranial hypertension, intracranial sinovenous occlusive diseases, and other neurologic syndromes.
Medication
Treatment is aimed toward individual symptoms as they occur. Medication is given to reduce the inflammatory response.
Anti-inflammatory agents
Systemically interfere with events leading to inflammation.
Colchicine
Decreases leukocyte motility and phagocytosis in inflammatory responses. Used to prevent recurrent attacks.
Adult
0.5-1 mg PO qd
Pediatric
Not established
Sympathomimetic agent toxicity and effect of CNS depressants are increased significantly with colchicine
Documented hypersensitivity; severe renal, hepatic, GI, or cardiac disorders; blood dyscrasias
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Risk of renal failure, hepatic failure, permanent hair loss, bone marrow suppression, numbness or tingling in hands and feet, disseminated intravascular coagulopathy, and decreased sperm count; dose-dependent GI upset is common
Corticosteroids
Systemic corticosteroids are not useful in the long-term management of Behçet disease. Some authors use corticosteroids as initial therapy especially in mild cases. However, other authorities state that there is no role for corticosteroids in the treatment of this disease. Systemic corticosteroids should be used only for short periods of time and probably in combination with immunosuppressive therapy. Topical or sub-Tenon corticosteroids have proven effective.
Prednisone (Deltasone, Orasone, Meticorten)
May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Use smallest dose for shortest duration to achieve therapeutic effect. Use in combination with immunosuppressive therapy. Also may use pulse IV therapy over a 3-day period.
Adult
1-1.5 mg/kg/d PO initially; taper after therapeutic effect achieved
Pediatric
Not established
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
Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used; use lowest effective dose; psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations; existing emotional instability or psychotic tendencies may be aggravated by corticosteroids
Avascular or aseptic necrosis of femoral head has been associated with long-term corticosteroid treatment and also has occurred in patients receiving high-dose short-term therapy (more likely to occur in patients with predisposing illness such as rheumatoid arthritis or systemic lupus erythematosus)
Enhanced effect of corticosteroids exists in patients with hypothyroidism and with cirrhosis; use aspirin and nonsteroidal anti-inflammatory agents cautiously in conjunction with corticosteroids in patients with hypoprothrombinemia; patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after stressful situation indicated; may mask signs of infection, and new infections may appear during their use; there may be decreased resistance and inability to localize infection when corticosteroids used; if corticosteroids have to be used in the presence of bacterial infections, institute appropriate anti-infective therapy
Prednisolone acetate 1% (Pred Forte)
Treats acute inflammations following eye surgery or other types of insults to eye. Decreases inflammation and corneal neovascularization. Suppresses migration of polymorphonuclear leukocytes and reverses increased capillary permeability. In cases of bacterial infections, concomitant use of anti-infective agents is mandatory; if signs and symptoms do not improve after 2 days, reevaluate patient. Dosing may be reduced, but advise patients not to discontinue therapy prematurely.
Useful for acute iritis. Frequent dosing (q1-2h) useful initially, followed by gradual taper.
Adult
1 gtt qid or greater depending on severity of uveitis
Pediatric
Not established
None reported
Documented hypersensitivity; viral, fungal, or tubercular infections
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Prolonged ophthalmic use may result in increased intraocular pressure in some individuals; if these products are used for 10 d or longer, monitor intraocular pressure; in diseases causing thinning of the cornea or sclera, perforation has been known to occur with use of topical preparations containing corticosteroids; protracted use of topical corticosteroids in the eye may result in the development of posterior subcapsular cataracts; in patients with a history of herpetic infection of the cornea, reactivation of the disease may occur with use of topical ophthalmic corticosteroids; shake eye suspensions well before use
Immunosuppressive agents
Used to treat acute attacks and reduce frequency of recurrences.
Cyclophosphamide (Cytoxan, Neosar)
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 cells. DOC for severe Behçet disease. Must be administered by an experienced clinician.
Adult
50-150 mg PO qd
Pediatric
Not established
Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; 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 anticoagulants; 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
Documented hypersensitivity; severely depressed bone marrow function
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Administer cautiously to patients with leukopenia, thrombocytopenia, tumor cell infiltration of bone marrow, previous x-ray therapy, previous therapy with other cytotoxic agents, impaired hepatic or renal function; because cyclophosphamide may exert a suppressive action in immune mechanisms, consider interruption or modification of dosage for patients who develop bacterial, fungal, or viral infections; this is especially true for patients receiving concomitant steroid therapy and perhaps those with a recent history of steroid therapy, since infections in some of these patients have been fatal; varicella-zoster infections appear to be particularly dangerous under these circumstances; it is recommended that patients being considered as candidates for long-term therapy have their renal function monitored prior to treatment; regularly examine urine for red cells that may precede hemorrhagic cystitis
Chlorambucil (Leukeran)
Aromatic nitrogen mustard derivative, which acts as a bifunctional alkylating agent. Alkylation takes place through the formation of a highly reactive ethylenimonium radical. Probable mode of action involves cross-linkage of the ethylenimonium derivative between 2 strands of helical DNA and subsequent interference with replication.
Adult
0.1 mg/kg PO qd for 3-6 wk; adjust dose depending on blood counts
Pediatric
Not established
None reported
Documented hypersensitivity; previous resistance to medication
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in history of seizure disorders or diagnosed with bone marrow suppression
Cyclosporine (Sandimmune)
Potent immunosuppressive agent with narrow therapeutic range, shown to decrease number and severity of attacks of Behçet disease.
Adult
2.5-5 mg/kg PO qd or divided bid
Pediatric
Not established
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
Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis since it may increase risk of cancer
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May cause increases in serum creatinine and urea levels, even at recommended doses as a result of reduced glomerular filtration rate (ie, nephrotoxicity); functional changes are dose dependent and reversible, and usually respond to dose reduction; although less frequent, some patients may develop structural changes in the kidney during long-term treatment; close monitoring of renal function is required; abnormal values may necessitate dose reduction; risk of renal structural changes is greater if serum creatinine level increases >30% from patient's baseline value; thus, regular measurements of serum creatinine levels are essential
More on Behcet Disease |
| Overview: Behcet Disease |
| Differential Diagnoses & Workup: Behcet Disease |
 Treatment & Medication: Behcet Disease |
| Follow-up: Behcet Disease |
| Multimedia: Behcet Disease |
| References |
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References
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Further Reading
Keywords
Behcet's disease, Behçet disease, Behçet’s disease aphthous ulcers, genital ulcers, uveitis, iridocyclitis, iritis, intraocular inflammation, oral ulceration, oral ulcers, Silk Road disease
