Ophthalmologic Manifestations of Behcet Disease Treatment & Management

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.^[7]

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. The extent of involvement and the severity of disease determine the choice of medication. Treatment options include corticosteroids, cytotoxic agents, cyclosporine, and colchicine. (See the image below.)

• 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 received systemic corticosteroids compared with 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 in an outpatient setting.
  • 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/d. 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/d 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 Behçet 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 associated with systemic corticosteroid therapy.
  • 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 patient.

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 the Multimedia section 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 fewer complete remissions are achieved, 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]
  • Tumor necrosis factor (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, because 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]

• Uveitis service if available
• Gastroenterologist
• Rheumatologist
• Neurologist: 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.