Fig. 12.27 Eales’ disease

presence is required according to the International Study Group for Behçet’s Disease. However, oral ulcers are very common in the general population and accompany many disorders. Therefore, not everyone who has had oral ulcers should be considered as having Behçet’s disease. Sarcoidosis and Reiter’s syndrome may also sometimes present with oral ulcers. Table 12.3 summarizes the most possible diseases in the differential diagnosis of ocular Behçet’s disease (Fig. 12.27).

Management of Ocular Disease

The aim of the treatment in ocular Behçet’s disease is to achieve a rapid resolution of inflammation, reduce frequency and severity of attacks, and to avoid complications. There is not a standard treatment protocol since the extent and severity of the disease and patient response to a certain medication determine the treatment required. A combination therapy is necessary in most cases. The management of patients with Behçet’s disease should be in collaboration with other specialties, and systemic administration of drugs should be conducted in consultation with an internist.

For acute, isolated anterior segment inflammation, frequent topical corticosteroids and mydriatics may be adequate. Posterior segment inflammation, however, is severe and progressive in the majority of patients and

requires systemic treatment [60]. Mild posterior segment inflammation may be managed by subTenon’s capsule corticosteroid injections, particularly if the disease is unilateral. For severe, recurrent, or unremitting posterior segment inflammation, systemic corticosteroids should be given with an extremely slow taper. In the absence of response to systemic corticosteroids within 2–3 months, either another type of medication should be added or treatment should be converted to another medication [60]. In patients with severe findings or aggressive course of the disease, immunosuppressive or immunomodulator therapy could be initiated immediately.

For patients with familial Behçet’s disease, poor ocular prognosis in a patient does not indicate aggressive treatment in his/her sibling and that each sibling should be managed on an individual bases [49].

Medical Treatment

Colchicine

There is abnormal leukocyte migration in Behçet’s disease, and colchicine—a drug that inhibits such migration by binding tubulin and inhibiting cell division—is effective in controlling skin and joint inflammation. However, it is inadequate in suppressing active ocular inflammation [61] and is used mostly to prevent recurrences of ocular inflammation. The optimum dosage of colchicine is 0.5–1.5 mg/day. The most common side effects of colchicine involve the gastrointestinal system with nausea, vomiting, abdominal pain, and diarrhea. It can cause bone marrow suppression. Therefore, all patients taking long-term colchicine require blood count monitoring. Colchicine can also cause hair loss, weakness, nerve irritation, decreased fertility, and azoospermia.

Corticosteroids

Corticosteroids are still the first choice of treatment in ocular Behçet’s patients to treat acute inflammation. Topical preparations are effective only for anterior chamber inflammation, while sub-Tenon’s capsule, intravitreal, and/or systemic

corticosteroids are commonly used for posterior segment inflammation. Systemic corticosteroids could either be given as oral daily (1 mg/kg/day initial dose) or less preferably as bolus infusion. However, despite being effective in decreasing acute inflammation, systemic corticosteroids alone often fail to prevent recurrences and therefore are frequently used in combination with other medications. The major side effects of corticosteroids are elevated intraocular pressure, cataract, gastrointestinal ulceration, hypertension, diabetes mellitus, electrolyte abnormalities, osteoporosis, and reduced resistance to infections [60].

Intravitreal Triamcinolone

Intravitreal triamcinolone acetonide (IVTA) has become a popular treatment and been reported to be effective in resolving the persistent CME and severe vitritis, as well as in preventing recurrences of resistant uveitis in patients with Behçet’s disease (Fig. 12.28) [40, 62–64]. However, the frequent side effects such as intraocular pressure elevation and cataract formation should be balanced with its positive effects.

Cyclosporin A and Tacrolimus (FK506)

Cyclosporin A and tacrolimus (FK506) are the two immunophilin ligands in clinical use today. They act within T cells by binding to cytoplasmic receptors termed immunophilins, thereby inhibiting the action of these cells and inducing a state of immunosuppression via a mechanism

entirely separate from corticosteroids [60]. Cyclosporin A is a potent immunoregulator of the cellular immune response and has been found to be effective in controlling the intraocular inflammation in Behçet’s disease [65]. It is given as an initial oral dose of 5 mg/kg/day. In patients who respond well, the dosage is gradually reduced over 3 months to a maintenance level of 2 mg/kg/ day. For those who respond poorly, the tapering period can be extended. Cyclosporin A has also been found to reduce the number and severity of extraocular symptoms. However, it should be kept in mind that recurrences are very common with the cessation of cyclosporin A.

Tacrolimus, a natural metabolite of the bacterium Streptomyces tsukubaensis, is 10–100 times more potent as an immunosuppressive agent than cyclosporine on a weight-for-weight basis [66]. Tacrolimus is not commonly used in the treatment of Behçet’s uveitis but has been reported to be effective in patients refractory to cyclosporin A [67]. It is used at doses of 0.03–0.08 mg/kg daily. The use of tacrolimus in the treatment of Behçet’s disease is yet to be fully established, but it is currently predominantly indicated for uveitis that is refractory to other medications [68].

Side effects such as hepatotoxicity, nephrotoxicity, hypertension, weakness, paresthesia, gastrointestinal manifestations, anemia, and gingival hyperplasia are seen with cyclosporin A and less with tacrolimus [69]. Combining lowdose corticosteroid and low-dose cyclosporine

may decrease the side effects of both drugs while maintaining their efficacy.

Interferon-a(alpha)

Interferon-a(alpha), a naturally occurring cytokine, was first used in the treatment of Behçet’s disease due to its antiviral activity against herpes simplex virus 1. Although the role of herpes simplex virus type 1 in the pathogenesis of Behçet’s disease could not be proven, the immunomodulatory properties of interferon- a(alpha) such as decreasing the number of circulating T cells, enhancing HLA-1 expression on peripheral monocytes from Behçet’s disease patients, and inhibiting T cell adhesion to endothelial cells in vitro lead to its use in the treatment of Behçet’s disease [70].

It is administered as subcutaneous or intramuscular injections of 3 to 18 × 106 units of interferon-alpha-2a or 3 to 5 × 106 units of inter- feron-alpha-2b daily or 3 times per week. Zouboulis and Orfanos [71] reviewed 22 original reports of 144 patients with Behçet’s disease to estimate the efficacy of interferon-alpha on mucocutaneous, ocular, and joint manifestations. Seventy-four percent of patients with mucocutaneous manifestations, 95% of patients with uveitis, and 93% of patients with arthropathy/arthritis exhibited a partial or complete response. Interferon-alpha-2a regimens were more effective than interferon-alpha-2b ones on mucocutaneous and ocular manifestations. Similar effects were also observed in a recent study with 91% partial or complete response with interferon therapy [72]. Recurrences, especially for uveitis is quite common after discontinuation of treatment.

A randomized placebo-controlled and doubleblind study also showed the efficacy of inter- feron-alpha-2a on oral ulcers, genital ulcers, papulopustular lesions, and ocular inflammation in patients with BD [73].

The most common side effects are influenzalike syndrome, increase in serum liver enzymes, and reversible leukopenia. Although lymphocytopenia, thrombocytopenia, ulcerations at the site of injection, alopecia, worsening of psoriasis, epileptic seizures, and autoantibodies or a

Behçet-like disease have been reported, interferon appears to be well tolerated and the side effects disappear after dose tapering [72, 74, 75]. A 3-month high-dose regimen (9 × 106 units three times per week) followed by a low maintenance dose (3 × 106 units three times per week) is recommended [71]. However, the optimum dosage and duration of interferon in the treatment of Behçet’s disease need to be determined.

Anti-tumor Necrosis Factor Treatment

Tumor necrosis factor-a(alpha) (TNF-a), a proinflammatory cytokine, plays a significant role in the pathogenesis of Behçet’s uveitis based on several evidences: increased serum and aqueous levels in Behçet’s patients compared to patients without Behçet’s uveitis, increased number of TNF-a(alpha)-producing cells during active disease, and its role in experimental models of uveitis [70, 76, 77]. Three TNF- a(alpha) inhibitors are currently used in inflammatory conditions: infliximab, a recombinant chimeric monoclonal antibody; adalimumab, a humanized monoclonal antibody; and the fusion protein human p75 TNF-a(alpha) receptor IgG1 etanercept [70].

Infliximab has been found to be effective in reducing the frequency of uveitis attacks, treating refractory macular edema, and improving the visual acuity especially in cases resistant to combination therapy with azathioprine, cyclosporine, and corticosteroids [72]. In addition, infliximab has a corticosteroid-sparing effect. Intravenous infusions of 5–10 mg/kg at weeks 0, 2, 6, and 10 or 14 have been used [72, 78]. However, controlled masked studies are warranted to determine the optimal dosage and duration in addition to co-medication interaction.

Etanercept has shown some efficacy for the mucocutaneous manifestations of Behçet’s disease in a randomized, double-blind, controlled trial using 25 mg subcutaneously twice a week [79]. However, the ocular effects were not evaluated in that study. Two children with BD uveitis were treated with etanercept, one with and one without a good result [80].